TY  - JOUR
AB  - PURPOSE: Neurodevelopmental disorders exhibit clinical and genetic heterogeneity, ergo manifest dysfunction in components of diverse cellular pathways; the precise pathomechanism for the majority remains elusive. METHODS: We studied five affected individuals from three unrelated families manifesting global developmental delay, postnatal microcephaly, and hypotonia. We employed exome sequencing and prioritized variants that were subsequently characterized using immunofluorescence, immunoblotting, pulldown assays, and RNA sequencing. RESULTS: We identified biallelic variants in ZFTRAF1, encoding a protein of yet unknown function. Four affected individuals from two unrelated families segregated two homozygous frameshift variants in ZFTRAF1, whereas, in the third family, an intronic splice site variant was detected. We investigated ZFTRAF1 at the cellular level and signified it as a nucleocytoplasmic protein in different human cell lines. ZFTRAF1 was completely absent in the fibroblasts of two affected individuals. We also identified 110 interacting proteins enriched in mRNA processing and autophagy-related pathways. Based on profiling of autophagy markers, patient-derived fibroblasts show irregularities in the protein degradation process. CONCLUSION: Thus, our findings suggest that biallelic variants of ZFTRAF1 cause a severe neurodevelopmental disorder.
AU  - Asif, M.*
AU  - Khayyat, A.I.A.*
AU  - Alawbathani, S.*
AU  - Abdullah, U.*
AU  - Sanner, A.*
AU  - Georgomanolis, T.*
AU  - Haasters, J.*
AU  - Becker, K.*
AU  - Budde, B.*
AU  - Becker, C.*
AU  - Thiele, H.*
AU  - Baig, S.M.*
AU  - Isidoro-García, M.*
AU  - Winter, D.*
AU  - Pogoda, H.M.*
AU  - Muhammad, S.*
AU  - Hammerschmidt, M.*
AU  - Kraft, F.*
AU  - Kurth, I.*
AU  - Martin, H.G.*
AU  - Wagner, M.
AU  - Nürnberg, P.*
AU  - Hussain, M.S.*
C1  - 70531
C2  - 55647
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
TI  - Biallelic loss-of-function variants of ZFTRAF1 cause neurodevelopmental disorder with microcephaly and hypotonia.
JO  - Genet. Med.
VL  - 26
IS  - 7
PB  - Elsevier Science Inc
PY  - 2024
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - PURPOSE: Imbalances in protein homeostasis affect human brain development, with the ubiquitin-proteasome system (UPS) and autophagy playing crucial roles in neurodevelopmental disorders (NDD). This study explores the impact of biallelic USP14 variants on neurodevelopment, focusing on its role as a key hub connecting UPS and autophagy. METHODS: Here, we identified biallelic USP14 variants in four individuals from three unrelated families: one fetus, a newborn with a syndromic NDD, and two siblings affected by a progressive neurological disease. Specifically, the two siblings from the latter family carried two compound heterozygous variants c.8T>C p.(Leu3Pro) and c.988C>T p.(Arg330*), while the fetus had a homozygous frameshift c.899_902del p.(Lys300Serfs*24) variant and the newborn patient harbored a homozygous frameshift c.233_236del p.(Leu78Glnfs*11) variant. Functional studies were conducted using SDS-PAGE, Western blotting, and mass spectrometry analyses in both patient-derived and CRISPR-Cas-generated cells. RESULTS: Our investigations indicated that the USP14 variants correlated with reduced N-terminal methionine excision, along with profound alterations in proteasome, autophagy, and mitophagy activities. CONCLUSION: Biallelic USP14 variants in NDD patients perturbed protein degradation pathways, potentially contributing to disorder etiology. Altered UPS, autophagy, and mitophagy activities underscore the intricate interplay, elucidating their significance in maintaining proper protein homeostasis during brain development.
AU  - Ebstein, F.*
AU  - Latypova, X.*
AU  - Hung, K.Y.S.*
AU  - Prado, M.A.*
AU  - Lee, B.H.*
AU  - Möller, S.*
AU  - Wendlandt, M.*
AU  - Zieba, B.A.*
AU  - Florenceau, L.*
AU  - Vignard, V.*
AU  - Poirier, L.*
AU  - Toutain, B.*
AU  - Moroni, I.*
AU  - Dubucs, C.*
AU  - Chassaing, N.*
AU  - Horvath, J.*
AU  - Prokisch, H.
AU  - Küry, S.*
AU  - Bézieau, S.*
AU  - Paulo, J.A.*
AU  - Finley, D.*
AU  - Krüger, E.*
AU  - Ghezzi, D.*
AU  - Isidor, B.*
C1  - 70263
C2  - 55476
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
TI  - Biallelic USP14 variants cause a syndromic neurodevelopmental disorder.
JO  - Genet. Med.
VL  - 26
IS  - 6
PB  - Elsevier Science Inc
PY  - 2024
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - PURPOSE: Rothmund-Thomson syndrome (RTS) is characterized by poikiloderma, sparse hair, small stature, skeletal defects, cancer, and cataracts, resembling features of premature aging. RECQL4 and ANAPC1 are the 2 known disease genes associated with RTS in >70% of cases. We describe RTS-like features in 5 individuals with biallelic variants in CRIPT (OMIM 615789). METHODS: Two newly identified and 4 published individuals with CRIPT variants were systematically compared with those with RTS using clinical data, computational analysis of photographs, histologic analysis of skin, and cellular studies on fibroblasts. RESULTS: All CRIPT individuals fulfilled the diagnostic criteria for RTS and additionally had neurodevelopmental delay and seizures. Using computational gestalt analysis, CRIPT individuals showed greatest facial similarity with individuals with RTS. Skin biopsies revealed a high expression of senescence markers (p53/p16/p21) and the senescence-associated ß-galactosidase activity was elevated in CRIPT-deficient fibroblasts. RECQL4- and CRIPT-deficient fibroblasts showed an unremarkable mitotic progression and unremarkable number of mitotic errors and no or only mild sensitivity to genotoxic stress by ionizing radiation, mitomycin C, hydroxyurea, etoposide, and potassium bromate. CONCLUSION: CRIPT causes an RTS-like syndrome associated with neurodevelopmental delay and epilepsy. At the cellular level, RECQL4- and CRIPT-deficient cells display increased senescence, suggesting shared molecular mechanisms leading to the clinical phenotypes.
AU  - Averdunk, L.*
AU  - Huetzen, M.A.*
AU  - Moreno-Andrés, D.*
AU  - Kalb, R.*
AU  - McKee, S.*
AU  - Hsieh, T.C.*
AU  - Seibt, A.*
AU  - Schouwink, M.*
AU  - Lalani, S.*
AU  - Faqeih, E.A.*
AU  - Brunet, T.
AU  - Boor, P.*
AU  - Neveling, K.*
AU  - Hoischen, A.*
AU  - Hildebrandt, B.*
AU  - Graf, E.*
AU  - Lu, L.*
AU  - Jin, W.*
AU  - Schaper, J.*
AU  - Omer, J.A.*
AU  - Demaret, T.*
AU  - Fleischer, N.*
AU  - Schindler, D.*
AU  - Krawitz, P.*
AU  - Mayatepek, E.*
AU  - Wieczorek, D.*
AU  - Wang, L.L.*
AU  - Antonin, W.*
AU  - Jachimowicz, R.D.*
AU  - von Felbert, V.*
AU  - Distelmaier, F.*
C1  - 67630
C2  - 53937
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
TI  - Biallelic variants in CRIPT cause a Rothmund-Thomson-like syndrome with increased cellular senescence.
JO  - Genet. Med.
VL  - 25
IS  - 7
PB  - Elsevier Science Inc
PY  - 2023
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - PURPOSE: RNF213, encoding a giant E3 ubiquitin ligase, has been recognized for its role as a key susceptibility gene for moyamoya disease (MMD). Case reports have also implicated specific variants in RNF213 with an early-onset form of MMD with full penetrance. We aimed to expand the phenotypic spectrum of monogenic RNF213-related disease and to evaluate genotype-phenotype correlations. METHODS: Patients were identified through reanalysis of exome sequencing (ES) data of an unselected cohort of unsolved pediatric cases and through GeneMatcher or ClinVar. Functional characterization was done by proteomics analysis and oxidative phosphorylation enzyme activities using patient derived fibroblasts. RESULTS: We identified 14 individuals from 13 unrelated families with (de novo) missense variants in RNF213 clustering within or around the RING domain. Individuals presented either with early-onset stroke (n=11) or with Leigh syndrome (n=3). No genotype-phenotype correlation could be established. Proteomics using patient derived fibroblasts revealed no significant differences between clinical subgroups. 3D-modeling revealed a clustering of missense variants in the tertiary structure of RNF213 potentially affecting Zinc-binding suggesting a gain-of-function or dominant negative effect. CONCLUSIONS: De novo missense variants in RNF213 clustering in the E3 RING or other regions affecting Zinc-binding lead to an early-onset syndrome characterized by stroke or Leigh syndrome.
AU  - Brunet, T.*
AU  - Zott, B.*
AU  - Lieftüchter, V.*
AU  - Lenz, D.*
AU  - Schmidt, A.*
AU  - Peters, P.*
AU  - Kopajtich, R.
AU  - Zaddach, M.*
AU  - Zimmermann, H.*
AU  - Hüning, I.*
AU  - Ballhausen, D.*
AU  - Staufner, C.*
AU  - Bianzano, A.*
AU  - Hughes, J.*
AU  - Taylor, R.W.*
AU  - McFarland, R.*
AU  - Devlin, A.*
AU  - Mihaljevic, M.*
AU  - Barišić, N.*
AU  - Rohlfs, M.*
AU  - Wilfling, S.*
AU  - Sondheimer, N.*
AU  - Hewson, S.*
AU  - Marinakis, N.M.*
AU  - Kosma, K.*
AU  - Traeger-Synodinos, J.*
AU  - Elbracht, M.*
AU  - Begemann, M.*
AU  - Trepels-Kottek, S.*
AU  - Hasan, D.*
AU  - Scala, M.*
AU  - Capra, V.*
AU  - Zara, F.*
AU  - van der Ven, A.T.*
AU  - Driemeyer, J.*
AU  - Apitz, C.*
AU  - Kramer, J.*
AU  - Strong, A.*
AU  - Hakonarson, H.*
AU  - Watson, D.*
AU  - Mayr, J.A.*
AU  - Prokisch, H.
AU  - Meitinger, T.*
AU  - Borggraefe, I.*
AU  - Spiegler, J.*
AU  - Baric, I.*
AU  - Paolini, M.*
AU  - Gerstl, L.*
AU  - Wagner, M.
C1  - 68725
C2  - 54934
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
TI  - De novo variants in RNF213 are associated with a clinical spectrum ranging from Leigh syndrome to early-onset stroke.
JO  - Genet. Med.
VL  - 26
IS  - 2
PB  - Elsevier Science Inc
PY  - 2023
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - PURPOSE: Clinical checklists are the standard of care to determine whether a child with cancer shows indications for genetic testing. Nevertheless, the efficacy of these tests to reliably detect genetic cancer predisposition in children with cancer is still insufficiently investigated. METHODS: We assessed the validity of clinically recognizable signs to identify cancer predisposition by correlating a state-of-the-art clinical checklist to the corresponding exome sequencing analysis in an unselected single-center cohort of 139 child-parent data sets. RESULTS: In total, one-third of patients had a clinical indication for genetic testing according to current recommendations, and 10.1% (14 of 139) of children harbored a cancer predisposition. Of these, 71.4% (10 of 14) were identified through the clinical checklist. In addition, >2 clinical findings in the checklist increased the likelihood to identifying genetic predisposition from 12.5% to 50%. Furthermore, our data revealed a high rate of genetic predisposition (40%, 4 of 10) in myelodysplastic syndrome cases, while no (likely) pathogenic variants were identified in the sarcoma and lymphoma group. CONCLUSION: In summary, our data show high checklist sensitivity, particularly in identifying childhood cancer predisposition syndromes. Nevertheless, the checklist used here also missed 29% of children with a cancer predisposition, highlighting the drawbacks of sole clinical evaluation and underlining the need for routine germline sequencing in pediatric oncology.
AU  - Friedrich, U.A.
AU  - Bienias, M.*
AU  - Zinke, C.*
AU  - Prazenicova, M.*
AU  - Lohse, J.*
AU  - Jahn, A.*
AU  - Menzel, M.*
AU  - Langanke, J.*
AU  - Walter, C.*
AU  - Wagener, R.*
AU  - Brozou, T.*
AU  - Varghese, J.*
AU  - Dugas, M.*
AU  - Erlacher, M.*
AU  - Schrock, E.*
AU  - Suttorp, M.*
AU  - Borkhardt, A.*
AU  - Hauer, J.*
AU  - Auer, F.*
C1  - 67768
C2  - 54246
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
TI  - A clinical screening tool to detect genetic cancer predisposition in pediatric oncology shows high sensitivity but can miss a substantial percentage of affected children.
JO  - Genet. Med.
VL  - 25
IS  - 8
PB  - Elsevier Science Inc
PY  - 2023
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - PURPOSE: SLC4A10 encodes a plasma membrane-bound transporter, which mediates Na+-dependent HCO3- import thus mediating net acid extrusion. Slc4a10 knockout (KO) mice show collapsed brain ventricles, an increased seizure threshold, mild behavioral abnormalities, impaired vision, and deafness. METHODS: Utilizing exome/genome sequencing in families with undiagnosed neurodevelopmental disorders (NDD) and international data sharing, 11 patients from 6 independent families with biallelic variants in SLC4A10 were identified. Clinico-radiological and dysmorphology assessments were conducted. A minigene assay, localization studies, intracellular pH recordings, and protein modelling were performed to study the possible functional consequences of the variant alleles. RESULTS: The families harbour 8 segregating ultra-rare biallelic SLC4A10 variants (7 missense and 1 splicing). Patients phenotypically exhibit global developmental delay/intellectual disability and central hypotonia associated with variable speech delay, microcephaly, cerebellar ataxia, epilepsy, and facial dysmorphism. Neuroimaging features range from some non-specific to distinct neuroradiological findings, including slit ventricles and a peculiar form of bilateral curvilinear nodular heterotopia. In-silico analyses showed 6/7 missense variants affect evolutionarily conserved residues. Functional analyses supported the pathogenicity of 4/7 missense variants. CONCLUSION: We provide evidence that pathogenic biallelic SLC4A10 variants can lead to NDD characterized by variable abnormalities of the central nervous system including altered brain ventricles thus resembling several features observed in KO mice.
AU  - Maroofian, R.*
AU  - Zamani, M.*
AU  - Kaiyrzhanov, R.*
AU  - Liebmann, L.*
AU  - Ghayoor Karimiani, E.*
AU  - Vona, B.*
AU  - Huebner, A.K.*
AU  - Calame, D.G.*
AU  - Misra, V.K.*
AU  - Sadeghian, S.*
AU  - Azizimalamiri, R.*
AU  - Mohammadi, M.H.*
AU  - Zeighami, J.*
AU  - Heydaran, S.*
AU  - Beiraghi Toosi, M.*
AU  - Akhondian, J.*
AU  - Babaei, M.*
AU  - Hashemi, N.*
AU  - Schnur, R.E.*
AU  - Suri, M.*
AU  - Setzke, J.*
AU  - Wagner, M.
AU  - Brunet, T.
AU  - Grochowski, C.M.*
AU  - Emrick, L.*
AU  - Chung, W.K.*
AU  - Hellmich, U.A.*
AU  - Schmidts, M.*
AU  - Lupski, J.R.*
AU  - Galehdari, H.*
AU  - Severino, M.*
AU  - Houlden, H.*
AU  - Hübner, C.A.*
C1  - 68948
C2  - 53787
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
TI  - Biallelic variants in SLC4A10 encoding the sodium-dependent chloride-bicarbonate exchanger NCBE lead to a neurodevelopmental disorder.
JO  - Genet. Med.
VL  - 26
IS  - 3
PB  - Elsevier Science Inc
PY  - 2023
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - Correction to: Genetics in Medicine 2022; https://doi.org/10.1016/j.gim.2022.07.006, published online 20 August 2022. In the article “Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy” (Genet Med 2022;24:2079–2090), the following update was made. Susan M. Downes and Andrea H. Németh have been added as authors for this article (see update authors’ list above). We have also updated the “Author Information” section with the contributions these two authors made to the article below. Conceptualization: J.P., A.T., V.C., H.Hengel, T.B.H., H.Houlden; Data Curation: J.P., A.T., V.C., H.Hengel; Data Analysis: J.P., A.T., V.C., H.Hengel, K.K, T.B.H., T.L., A.V., E.G., L.V., N.D., M.R., J.A., B.M., I.C., S.O., T.M.S., M.S., D.S.; Patients Recruitment and Phenotypic Characterization: J.P., A.T., H.Hengel, L.S., H.Houlden., J.S., M.B., E.C., R.M., G.-A.H., C.B., N.J.H.v.O., R.H., P.F.C., M.Y.T., C.H., M.H., G.K.T., N.W.W., S.N.H., F.B., J.K.K., C.B., B.vd.W., H.L., M.S., D.T., M.E.W., H.P.N. S.M.D., A.H.N.; Methodology: J.P., A.T., V.C., H.Hengel, G.D., C.R., A.V., B.M.; Supervision: L.S., H.Hen- gel, T.B.H., H.Houlden; Visualization: J.P., H.Hengel., J.A.; Writing-original draft: J.P., A.T., V.C., H.Hengel; Writing- review and editing: J.P., A.T., V.C., H.Hengel, O.R., T.B.H., L.S., H.Houlden. All authors revised the manuscript for intellectual content. The authors would like to apologize for any inconvenience this may have caused. The article has been corrected online and can be accessed at https://doi.org/10.1016/j.gim.2022.07.006.
AU  - Park, J.*
AU  - Tucci, A.*
AU  - Cipriani, V.*
AU  - Demidov, G.*
AU  - Rocca, C.*
AU  - Senderek, J.*
AU  - Butryn, M.*
AU  - Velic, A.*
AU  - Lam, T.*
AU  - Galanaki, E.*
AU  - Cali, E.*
AU  - Vestito, L.*
AU  - Maroofian, R.*
AU  - Deininger, N.*
AU  - Rautenberg, M.*
AU  - Admard, J.*
AU  - Hahn, G.A.*
AU  - Bartels, C.*
AU  - van Os, N.J.H.*
AU  - Horvath, R.*
AU  - Chinnery, P.F.*
AU  - Tiet, M.Y.*
AU  - Hewamadduma, C.*
AU  - Hadjivassiliou, M.*
AU  - Downes, S.M.*
AU  - Németh, A.H.*
AU  - Tofaris, G.K.*
AU  - Wood, N.W.*
AU  - Hayer, S.N.*
AU  - Bender, F.*
AU  - Menden, B.*
AU  - Cordts, I.*
AU  - Klein, K.*
AU  - Nguyen, H.P.*
AU  - Krauss, J.K.*
AU  - Blahak, C.*
AU  - Strom, T.M.
AU  - Sturm, M.*
AU  - van de Warrenburg, B.*
AU  - Lerche, H.*
AU  - Macek, B.*
AU  - Synofzik, M.*
AU  - Ossowski, S.*
AU  - Timmann, D.*
AU  - Wolf, M.E.*
AU  - Smedley, D.*
AU  - Riess, O.*
AU  - Schöls, L.*
AU  - Houlden, H.*
AU  - Haack, T.*
AU  - Hengel, H.*
C1  - 68309
C2  - 54741
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
TI  - Erratum: Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy (Genetics in Medicine (2022) 24(10) (2079–2090), (S1098360022008437), (10.1016/j.gim.2022.07.006)).
JO  - Genet. Med.
VL  - 25
IS  - 10
PB  - Elsevier Science Inc
PY  - 2023
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - Purpose: ATP2B2 encodes the variant-constrained plasma-membrane calcium-transporting ATPase-2, expressed in sensory ear cells and specialized neurons. ATP2B2/Atp2b2 variants were previously linked to isolated hearing loss in patients and neurodevelopmental deficits with ataxia in mice. We aimed to establish the association between ATP2B2 and human neurological disorders. Methods: Multinational case recruitment, scrutiny of trio-based genomics data, in silico analyses, and functional variant characterization were performed. Results: We assembled 7 individuals harboring rare, predicted deleterious heterozygous ATP2B2 variants. The alleles comprised 5 missense substitutions that affected evolutionarily conserved sites and 2 frameshift variants in the penultimate exon. For 6 variants, a de novo status was confirmed. Unlike described patients with hearing loss, the individuals displayed a spectrum of neurological abnormalities, ranging from ataxia with dystonic features to complex neurodevelopmental manifestations with intellectual disability, autism, and seizures. Two cases with recurrent amino-acid variation showed distinctive overlap with cerebellar atrophy-associated ataxia and epilepsy. In cell-based studies, all variants caused significant alterations in cytosolic calcium handling with both loss- and gain-of-function effects. Conclusion: Presentations in our series recapitulate key phenotypic aspects of Atp2b2-mouse models and underline the importance of precise calcium regulation for neurodevelopment and cerebellar function. Our study documents a role for ATP2B2 variants in causing heterogeneous neurodevelopmental and movement-disorder syndromes.
AU  - Poggio, E.*
AU  - Barazzuol, L.*
AU  - Salmaso, A.*
AU  - Milani, C.*
AU  - Deligiannopoulou, A.*
AU  - Cazorla, Á.G.*
AU  - Jang, S.S.*
AU  - Juliá-Palacios, N.*
AU  - Keren, B.*
AU  - Kopajtich, R.
AU  - Lynch, S.A.*
AU  - Mignot, C.*
AU  - Moorwood, C.*
AU  - Neuhofer, C.
AU  - Nigro, V.*
AU  - Oostra, A.*
AU  - Prokisch, H.
AU  - Saillour, V.*
AU  - Schuermans, N.*
AU  - Torella, A.*
AU  - Verloo, P.*
AU  - Yazbeck, E.*
AU  - Zollino, M.*
AU  - Jech, R.*
AU  - Winkelmann, J.
AU  - Necpál, J.*
AU  - Calì, T.*
AU  - Brini, M.*
AU  - Zech, M.
C1  - 68178
C2  - 54730
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
TI  - ATP2B2 de novo variants as a cause of variable neurodevelopmental disorders that feature dystonia, ataxia, intellectual disability, behavioral symptoms, and seizures.
JO  - Genet. Med.
VL  - 25
IS  - 12
PB  - Elsevier Science Inc
PY  - 2023
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - Purpose: Nonmuscle myosin II complexes are master regulators of actin dynamics that play essential roles during embryogenesis with vertebrates possessing 3 nonmuscle myosin II heavy chain genes, MYH9, MYH10, and MYH14. As opposed to MYH9 and MYH14, no recognizable disorder has been associated with MYH10. We sought to define the clinical characteristics and molecular mechanism of a novel autosomal dominant disorder related to MYH10. Methods: An international collaboration identified the patient cohort. CAS9-mediated knockout cell models were used to explore the mechanism of disease pathogenesis. Results: We identified a cohort of 16 individuals with heterozygous MYH10 variants presenting with a broad spectrum of neurodevelopmental disorders and variable congenital anomalies that affect most organ systems and were recapitulated in animal models of altered MYH10 activity. Variants were typically de novo missense changes with clustering observed in the motor domain. MYH10 knockout cells showed defects in primary ciliogenesis and reduced ciliary length with impaired Hedgehog signaling. MYH10 variant overexpression produced a dominant-negative effect on ciliary length. Conclusion: These data presented a novel genetic cause of isolated and syndromic neurodevelopmental disorders related to heterozygous variants in the MYH10 gene with implications for disrupted primary cilia length control and altered Hedgehog signaling in disease pathogenesis.
AU  - Holtz, A.M.*
AU  - Vancoil, R.*
AU  - Vansickle, E.A.*
AU  - Carere, D.A.*
AU  - Withrow, K.*
AU  - Torti, E.*
AU  - Juusola, J.*
AU  - Millan, F.*
AU  - Person, R.*
AU  - Guillen Sacoto, M.J.*
AU  - Si, Y.*
AU  - Wentzensen, I.M.*
AU  - Pugh, J.*
AU  - Vasileiou, G.*
AU  - Rieger, M.*
AU  - Reis, A.*
AU  - Argilli, E.*
AU  - Sherr, E.H.*
AU  - Aldinger, K.A.*
AU  - Dobyns, W.B.*
AU  - Brunet, T.
AU  - Hoefele, J.*
AU  - Wagner, M.
AU  - Haber, B.*
AU  - Kotzaeridou, U.*
AU  - Keren, B.*
AU  - Heron, D.*
AU  - Mignot, C.*
AU  - Heide, S.*
AU  - Courtin, T.*
AU  - Buratti, J.*
AU  - Murugasen, S.*
AU  - Donald, K.A.*
AU  - O'Heir, E.*
AU  - Moody, S.*
AU  - Kim, K.H.*
AU  - Burton, B.K.*
AU  - Yoon, G.*
AU  - Campo, M.d.*
AU  - Masser-Frye, D.*
AU  - Kozenko, M.*
AU  - Parkinson, C.*
AU  - Sell, S.L.*
AU  - Gordon, P.L.*
AU  - Prokop, J.W.*
AU  - Karaa, A.*
AU  - Bupp, C.*
AU  - Raby, B.A.*
C1  - 65950
C2  - 52998
SP  - 2065-2078
TI  - Heterozygous variants in MYH10 associated with neurodevelopmental disorders and congenital anomalies with evidence for primary cilia-dependent defects in Hedgehog signaling.
JO  - Genet. Med.
VL  - 24
IS  - 10
PY  - 2022
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - Purpose: CTR9 is a subunit of the PAF1 complex (PAF1C) that plays a crucial role in transcription regulation by binding CTR9 to RNA polymerase II. It is involved in transcription-coupled histone modification through promoting H3K4 and H3K36 methylation. We describe the clinical and molecular studies in 13 probands, harboring likely pathogenic CTR9 missense variants, collected through GeneMatcher. Methods: Exome sequencing was performed in all individuals. CTR9 variants were assessed through 3-dimensional modeling of the activated human transcription complex Pol II-DSIF-PAF-SPT6 and the PAF1/CTR9 complex. H3K4/H3K36 methylation analysis, mitophagy assessment based on tetramethylrhodamine ethyl ester perchlorate immunofluorescence, and RNA-sequencing in skin fibroblasts from 4 patients was performed. Results: Common clinical findings were variable degrees of intellectual disability, hypotonia, joint hyperlaxity, speech delay, coordination problems, tremor, and autism spectrum disorder. Mild dysmorphism and cardiac anomalies were less frequent. For 11 CTR9 variants, de novo occurrence was shown. Three-dimensional modeling predicted a likely disruptive effect of the variants on local CTR9 structure and protein interaction. Additional studies in fibroblasts did not unveil the downstream functional consequences of the identified variants. Conclusion: We describe a neurodevelopmental disorder caused by (mainly) de novo variants in CTR9, likely affecting PAF1C function.
AU  - Meuwissen, M.*
AU  - Verstraeten, A.*
AU  - Ranza, E.*
AU  - Iwaszkiewicz, J.*
AU  - Bastiaansen, M.*
AU  - Mateiu, L.*
AU  - Nemegeer, M.*
AU  - Meester, J.A.N.*
AU  - Afenjar, A.*
AU  - Amaral, M.*
AU  - Ballhausen, D.*
AU  - Barnett, S.*
AU  - Barth, M.*
AU  - Asselbergh, B.*
AU  - Spaas, K.*
AU  - Heeman, B.*
AU  - Bassetti, J.*
AU  - Blackburn, P.*
AU  - Schaer, M.*
AU  - Blanc, X.*
AU  - Zoete, V.*
AU  - Casas, K.*
AU  - Courtin, T.*
AU  - Doummar, D.*
AU  - Guerry, F.*
AU  - Keren, B.*
AU  - Pappas, J.*
AU  - Rabin, R.*
AU  - Begtrup, A.*
AU  - Shinawi, M.*
AU  - Vulto-van Silfhout, A.T.*
AU  - Kleefstra, T.*
AU  - Wagner, M.
AU  - Ziegler, A.*
AU  - Schaefer, E.*
AU  - Gérard, B.*
AU  - De Bie, C.I.*
AU  - Holwerda, S.J.B.*
AU  - Abbot, M.A.*
AU  - Antonarakis, S.E.*
AU  - Loeys, B.*
C1  - 64971
C2  - 52593
SP  - 1583-1591
TI  - Heterozygous variants in CTR9, which encodes a major component of the PAF1 complex, are associated with a neurodevelopmental disorder.
JO  - Genet. Med.
VL  - 24
IS  - 7
PY  - 2022
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - PURPOSE: RABGAP1 is a GTPase-activating protein implicated in a variety of cellular and molecular processes, including mitosis, cell migration, vesicular trafficking, and mTOR signaling. There are no known Mendelian diseases caused by variants in RABGAP1. METHODS: Through GeneMatcher, we identified 5 patients from 3 unrelated families with homozygous variants in the RABGAP1 gene found on exome sequencing. We established lymphoblastoid cells lines derived from an affected individual and her parents and performed RNA sequencing and functional studies. Rabgap1 knockout mice were generated and phenotyped. RESULTS: We report 5 patients presenting with a common constellation of features, including global developmental delay/intellectual disability, microcephaly, bilateral sensorineural hearing loss, and seizures, as well as overlapping dysmorphic features. Neuroimaging revealed common features, including delayed myelination, white matter volume loss, ventriculomegaly, and thinning of the corpus callosum. Functional analysis of patient cells revealed downregulated mTOR signaling and abnormal localization of early endosomes and lysosomes. Rabgap1 knockout mice exhibited several features in common with the patient cohort, including microcephaly, thinning of the corpus callosum, and ventriculomegaly. CONCLUSION: Collectively, our results provide evidence of a novel neurodevelopmental syndrome caused by biallelic loss-of-function variants in RABGAP1.
AU  - Oh, R.Y.*
AU  - Deshwar, A.R.*
AU  - Marwaha, A.*
AU  - Sabha, N.*
AU  - Tropak, M.*
AU  - Hou, H.*
AU  - Yuki, K.E.*
AU  - Wilson, M.D.*
AU  - Rump, P.*
AU  - Lunsing, R.*
AU  - Elserafy, N.*
AU  - Chung, C.W.T.*
AU  - Hewson, S.*
AU  - Klein-Rodewald, T.
AU  - Calzada-Wack, J.
AU  - Sanz-Moreno, A.
AU  - Kraiger, M.
AU  - Marschall, S.
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
AU  - Dowling, J.J.*
AU  - Schulze, A.*
C1  - 66153
C2  - 52633
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 2399-2407
TI  - Biallelic loss-of-function variants in RABGAP1 cause a novel neurodevelopmental syndrome.
JO  - Genet. Med.
VL  - 24
IS  - 11
PB  - Elsevier Science Inc
PY  - 2022
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - Purpose: Biallelic variants in UCHL1 have been associated with a progressive early-onset neurodegenerative disorder, autosomal recessive spastic paraplegia type 79. In this study, we investigated heterozygous UCHL1 variants on the basis of results from cohort-based burden analyses. Methods: Gene-burden analyses were performed on exome and genome data of independent cohorts of patients with hereditary ataxia and spastic paraplegia from Germany and the United Kingdom in a total of 3169 patients and 33,141 controls. Clinical data of affected individuals and additional independent families were collected and evaluated. Patients’ fibroblasts were used to perform mass spectrometry-based proteomics. Results: UCHL1 was prioritized in both independent cohorts as a candidate gene for an autosomal dominant disorder. We identified a total of 34 cases from 18 unrelated families, carrying 13 heterozygous loss-of-function variants (15 families) and an inframe insertion (3 families). Affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17). The mass spectrometry-based proteomics showed approximately 50% reduction of UCHL1 expression in patients’ fibroblasts. Conclusion: Our bioinformatic analysis, in-depth clinical and genetic workup, and functional studies established haploinsufficiency of UCHL1 as a novel disease mechanism in spastic ataxia.
AU  - Park, J.*
AU  - Tucci, A.*
AU  - Cipriani, V.*
AU  - Demidov, G.*
AU  - Rocca, C.*
AU  - Senderek, J.*
AU  - Velic, A.*
AU  - Lam, T.H.*
AU  - Galanaki, E.*
AU  - Cali, E.*
AU  - Vestito, L.*
AU  - Maroofian, R.*
AU  - Deininger, N.*
AU  - Rautenberg, M.*
AU  - Admard, J.*
AU  - Hahn, G.A.*
AU  - Bartels, C.*
AU  - van Os, N.J.H.*
AU  - Horvath, R.*
AU  - Chinnery, P.F.*
AU  - Tiet, M.Y.*
AU  - Hewamadduma, C.*
AU  - Hadjivassiliou, M.*
AU  - Tofaris, G.K.*
AU  - Wood, S.M.*
AU  - Zarowiecki, M.*
AU  - Wood, N.W.*
AU  - Hayer, S.N.*
AU  - Krauss, J.L.*
AU  - Strom, T.M.
AU  - Sturm, M.*
AU  - van de Warrenburg, B.P.*
AU  - Lerche, H.*
AU  - Synofzik, M.*
AU  - Ossowski, S.*
AU  - Timmann, D.*
AU  - Smedley, D.*
AU  - Riess, O.*
AU  - Schöls, L.*
AU  - Houlden, H.*
AU  - Haack, T.B.*
AU  - Hengel, H.*
C1  - 65945
C2  - 52994
SP  - 2079-2090
TI  - Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy.
JO  - Genet. Med.
VL  - 24
IS  - 10
PY  - 2022
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - Purpose: The study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and to determine the role of cysteine supplementation in its treatment. Methods: Individuals with biallelic (likely) pathogenic variants in TRMU were studied through an international retrospective collection of de-identified patient data. Results: In 62 individuals, including 30 previously unreported cases, we described 48 (likely) pathogenic TRMU variants, of which, 18 were novel. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals, 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency. Conclusion: In most patients, TRMU-associated ALF is a transient, reversible disease and cysteine supplementation improved survival.
AU  - Vogel, G.F.*
AU  - Mozer-Glassberg, Y.*
AU  - Landau, Y.E.*
AU  - Schlieben, L.D.
AU  - Prokisch, H.
AU  - Feichtinger, R.G.*
AU  - Mayr, J.A.*
AU  - Brennenstuhl, H.*
AU  - Schröter, J.*
AU  - Pechlaner, A.*
AU  - Alkuraya, F.S.*
AU  - Baker, J.J.*
AU  - Barcia, G.*
AU  - Baric, I.*
AU  - Braverman, N.*
AU  - Burnyte, B.*
AU  - Christodoulou, J.*
AU  - Ciara, E.*
AU  - Coman, D.*
AU  - Das, A.M.*
AU  - Darin, N.*
AU  - Della Marina, A.*
AU  - Distelmaier, F.*
AU  - Eklund, E.A.*
AU  - Ersoy, M.*
AU  - Fang, W.*
AU  - Gaignard, P.*
AU  - Ganetzky, R.D.*
AU  - Gonzales, E.*
AU  - Howard, C.R.*
AU  - Hughes, J.*
AU  - Konstantopoulou, V.*
AU  - Kose, M.*
AU  - Kerr, M.*
AU  - Khan, A.*
AU  - Lenz, D.*
AU  - McFarland, R.*
AU  - Margolis, M.G.*
AU  - Morrison, K.*
AU  - Müller, T.*
AU  - Murayama, K.*
AU  - Nicastro, E.*
AU  - Pennisi, A.*
AU  - Peters, H.*
AU  - Piekutowska-Abramczuk, D.*
AU  - Rötig, A.*
AU  - Santer, R.*
AU  - Scaglia, F.*
AU  - Schiff, M.*
AU  - Shagrani, M.*
AU  - Sharrard, M.*
AU  - Soler-Alfonso, C.*
AU  - Staufner, C.*
AU  - Storey, I.*
AU  - Stormon, M.*
AU  - Taylor, R.W.*
AU  - Thorburn, D.R.*
AU  - Teles, E.L.*
AU  - Wang, J.S.*
AU  - Weghuber, D.*
AU  - Wortmann, S.*
C1  - 66591
C2  - 53231
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
TI  - Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants.
JO  - Genet. Med.
VL  - 25
IS  - 6
PB  - Elsevier Science Inc
PY  - 2022
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - Purpose We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Methods Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. Results We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined. Conclusion Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals.
AU  - Brunet, T.*
AU  - McWalter, K.*
AU  - Mayerhanser, K.*
AU  - Anbouba, G.M.*
AU  - Armstrong-Javors, A.*
AU  - Bader, I.*
AU  - Baugh, E.*
AU  - Begtrup, A.*
AU  - Bupp, C.P.*
AU  - Callewaert, B.L.*
AU  - Cereda, A.*
AU  - Cousin, M.A.*
AU  - Jimenez, J.C.D.R.*
AU  - Demmer, L.*
AU  - Dsouza, N.R.*
AU  - Fleischer, N.*
AU  - Gavrilova, R.H.*
AU  - Ghate, S.*
AU  - Graf, E.
AU  - Green, A.*
AU  - Green, S.R.*
AU  - Iascone, M.*
AU  - Kdissa, A.*
AU  - Klee, D.*
AU  - Klee, E.W.*
AU  - Lancaster, E.*
AU  - Lindström, K.*
AU  - Mayr, J.A.*
AU  - McEntagart, M.*
AU  - Meeks, N.J.L.*
AU  - Mittag, D.*
AU  - Moore, H.*
AU  - Olsen, A.K.*
AU  - Ortiz, D.*
AU  - Parsons, G.*
AU  - Pena, L.D.M.*
AU  - Person, R.E.*
AU  - Punj, S.*
AU  - Ramos-Rivera, G.A.*
AU  - Sacoto, M.J.G.*
AU  - Bradley Schaefer, G.*
AU  - Schnur, R.E.*
AU  - Scott, T.M.*
AU  - Scott, D.A.*
AU  - Serbinski, C.R.*
AU  - Shashi, V.*
AU  - Siu, V.M.*
AU  - Stadheim, B.F.*
AU  - Sullivan, J.A.*
AU  - Švantnerová, J.*
AU  - Velsher, L.*
AU  - Wargowski, D.S.*
AU  - Wentzensen, I.M.*
AU  - Wieczorek, D.*
AU  - Winkelmann, J.
AU  - Yap, P.*
AU  - Zech, M.
AU  - Zimmermann, M.T.*
AU  - Meitinger, T.*
AU  - Distelmaier, F.*
AU  - Wagner, M.
C1  - 60528
C2  - 49337
CY  - Campus, 4 Crinan St, London, N1 9xw, England
SP  - 384–395
TI  - Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder.
JO  - Genet. Med.
VL  - 23
PB  - Springernature
PY  - 2021
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - PURPOSE: To investigate the effect of PLXNA1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and to functionally characterize the zebrafish homologs plxna1a and plxna1b during development. METHODS: We assembled ten patients from seven families with biallelic or de novo PLXNA1 variants. We describe genotype-phenotype correlations, investigated the variants by structural modeling, and used Morpholino knockdown experiments in zebrafish to characterize the embryonic role of plxna1a and plxna1b. RESULTS: Shared phenotypic features among patients include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Notably, seizures were predominantly reported in patients with monoallelic variants. Structural modeling of missense variants in PLXNA1 suggests distortion in the native protein. Our zebrafish studies enforce an embryonic role of plxna1a and plxna1b in the development of the central nervous system and the eye. CONCLUSION: We propose that different biallelic and monoallelic variants in PLXNA1 result in a novel neurodevelopmental syndrome mainly comprising developmental delay, brain, and eye anomalies. We hypothesize that biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect.
AU  - Dworschak, G.C.*
AU  - Punetha, J.*
AU  - Kalanithy, J.C.*
AU  - Mingardo, E.*
AU  - Erdem, H.B.*
AU  - Akdemir, Z.C.*
AU  - Karaca, E.*
AU  - Mitani, T.*
AU  - Marafi, D.*
AU  - Fatih, J.M.*
AU  - Jhangiani, S.N.*
AU  - Hunter, J.V.*
AU  - Dakal, T.C.*
AU  - Dhabhai, B.*
AU  - Dabbagh, O.*
AU  - Alsaif, H.S.*
AU  - Alkuraya, F.S.*
AU  - Maroofian, R.*
AU  - Houlden, H.*
AU  - Efthymiou, S.*
AU  - Dominik, N.*
AU  - Salpietro,V.*
AU  - Sultan, T.*
AU  - Haider, S.*
AU  - Bibi, F.*
AU  - Thiele, H.*
AU  - Hoefele, J.*
AU  - Riedhammer, K.M.*
AU  - Wagner, M.
AU  - Guella, I.*
AU  - Demos, M.*
AU  - Keren, B.*
AU  - Buratti, J.*
AU  - Charles, P.*
AU  - Nava, C.*
AU  - Heron, D.*
AU  - Heide, S.*
AU  - Valkanas, E.*
AU  - Waddell, L.B.*
AU  - Jones, K.J.*
AU  - Oates, E.C.*
AU  - Cooper, S.T.*
AU  - MacArthur, D.*
AU  - Syrbe, S.*
AU  - Ziegler, A.*
AU  - Platzer, K.*
AU  - Okur, V.*
AU  - Chung, W.K.*
AU  - O'Shea, S.A.*
AU  - Alcalay, R.*
AU  - Fahn, S.*
AU  - Mark, P.R.*
AU  - Guerrini, R.*
AU  - Vetro, A.*
AU  - Hudson, B.*
AU  - Schnur, R.E.*
AU  - Hoganson, G.E.*
AU  - Burton, J.E.*
AU  - McEntagart, M.*
AU  - Lindenberg, T.*
AU  - Yilmaz, Ö.*
AU  - Odermatt, B.*
AU  - Pehlivan, D.*
AU  - Posey, J.E.*
AU  - Lupski, J.R.*
AU  - Reutter, H.*
C1  - 62218
C2  - 50732
CY  - Campus, 4 Crinan St, London, N1 9xw, England
SP  - 1715–1725
TI  - Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies.
JO  - Genet. Med.
VL  - 23
PB  - Springernature
PY  - 2021
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - Unfortunately, in the first sentence in the abstract, a spelling mistake was introduced during the production process after our proofreading. The wording was changed from “aims” to “aimsed.” Heather M. McLaughlin was not listed among the authors. The original article has been corrected.
AU  - Klöckner, C.*
AU  - Sticht, H.*
AU  - Zacher, P.*
AU  - Popp, B.*
AU  - Babcock, H.E.*
AU  - Bakker, D.P.*
AU  - Barwick, K.*
AU  - Bonfert, M.V.*
AU  - Bönnemann, C.G.*
AU  - Brilstra, E.H.*
AU  - Chung, W.K.*
AU  - Clarke, A.J.*
AU  - Devine, P.*
AU  - Donkervoort, S.*
AU  - Fraser, J.L.*
AU  - Friedman, J.*
AU  - Gates, A.*
AU  - Ghoumid, J.*
AU  - Hobson, E.*
AU  - Horvath, G.*
AU  - Keller-Ramey, J.*
AU  - Keren, B.*
AU  - Kurian, M.A.*
AU  - Lee, V.*
AU  - Leppig, K.A.*
AU  - Lundgren, J.*
AU  - McDonald, M.T.*
AU  - McLaughlin, H.M.*
AU  - McTague, A.*
AU  - Mefford, H.C.*
AU  - Mignot, C.*
AU  - Mikati, M.A.*
AU  - Nava, C.*
AU  - Raymond, F.L.*
AU  - Sampson, J.R.*
AU  - Sanchis-Juan, A.*
AU  - Shashi, V.*
AU  - Shieh, J.T.C.*
AU  - Shinawi, M.*
AU  - Slavotinek, A.*
AU  - Stödberg, T.*
AU  - Stong, N.*
AU  - Sullivan, J.A.*
AU  - Taylor, A.C.*
AU  - Toler, T.L.*
AU  - van den Boogaard, M.J.*
AU  - van der Crabben, S.N.*
AU  - van Gassen, K.L.I.*
AU  - van Jaarsveld, R.H.*
AU  - Van Ziffle, J.*
AU  - Wadley, A.F.*
AU  - Wagner, M.
AU  - Wigby, K.*
AU  - Wortmann, S.B.*
AU  - Zarate, Y.A.*
AU  - Møller, R.S.*
AU  - Lemke, J.R.*
AU  - Platzer, K.*
C1  - 61433
C2  - 50201
TI  - Correction to: De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy.
JO  - Genet. Med.
VL  - 23
IS  - 4
PY  - 2021
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - Purpose: Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized. Methods: We describe 22 individuals from 19 unrelated families with biallelic variants in PIGG. We analyzed GPI-AP surface levels on granulocytes and fibroblasts for three and two individuals, respectively. We demonstrated enzymatic activity defects for PIGG variants in vitro in a PIGG/PIGO double knockout system. Results: Phenotypic analysis of reported individuals reveals shared PIGG deficiency–associated features. All tested GPI-APs were unchanged on granulocytes whereas CD73 level in fibroblasts was decreased. In addition to classic IGD symptoms such as hypotonia, intellectual disability/developmental delay (ID/DD), and seizures, individuals with PIGG variants of null or severely decreased activity showed cerebellar atrophy, various neurological manifestations, and mitochondrial dysfunction, a feature increasingly recognized in IGDs. Individuals with mildly decreased activity showed autism spectrum disorder. Conclusion: This in vitro system is a useful method to validate the pathogenicity of variants in PIGG and to study PIGG physiological functions.
AU  - Tremblay-Laganière, C.*
AU  - Maroofian, R.*
AU  - Nguyen, T.T.M.*
AU  - Karimiani, E.G.*
AU  - Kirmani, S.*
AU  - Akbar, F.*
AU  - Ibrahim, S.*
AU  - Afroze, B.*
AU  - Doosti, M.*
AU  - Ashrafzadeh, F.*
AU  - Babaei, M.*
AU  - Efthymiou, S.*
AU  - Christoforou, M.*
AU  - Sultan, T.*
AU  - Ladda, R.L.*
AU  - McLaughlin, H.M.*
AU  - Truty, R.*
AU  - Mahida, S.*
AU  - Cohen, J.S.*
AU  - Baranano, K.*
AU  - Ismail, F.Y.*
AU  - Patel, M.S.*
AU  - Lehman, A.*
AU  - Edmondson, A.C.*
AU  - Nagy, A.*
AU  - Walker, M.A.*
AU  - Mercimek-Andrews, S.*
AU  - Maki, Y.*
AU  - Sachdev, R.*
AU  - Macintosh, R.*
AU  - Palmer, E.E.*
AU  - Mancini, G.M.S.*
AU  - Barakat, T.S.*
AU  - Steinfeld, R.*
AU  - Rüsch, C.T.*
AU  - Stettner, G.M.*
AU  - Wagner, M.
AU  - Wortmann, S.B.*
AU  - Kini, U.*
AU  - Brady, A.F.*
AU  - Stals, K.L.*
AU  - Ismayilova, N.*
AU  - Ellard, S.*
AU  - Bernardo, D.*
AU  - Nugent, K.*
AU  - McLean, S.D.*
AU  - Antonarakis, S.E.*
AU  - Houlden, H.*
AU  - Kinoshita, T.*
AU  - Campeau, P.M.*
AU  - Murakami, Y.*
C1  - 62258
C2  - 50753
CY  - Campus, 4 Crinan St, London, N1 9xw, England
SP  - 1873-1881
TI  - PIGG variant pathogenicity assessment reveals characteristic features within 19 families.
JO  - Genet. Med.
VL  - 23
IS  - 10
PB  - Springernature
PY  - 2021
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - PURPOSE: To investigate monoallelic CLPB variants. Pathogenic variants in many genes cause congenital neutropenia. While most patients exhibit isolated hematological involvement, biallelic CLPB variants underlie a neurological phenotype ranging from nonprogressive intellectual disability to prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, 3-methylglutaconic aciduria, and neutropenia. CLPB was recently shown to be a mitochondrial refoldase; however, the exact function remains elusive. METHODS: We investigated six unrelated probands from four countries in three continents, with neutropenia and a phenotype dominated by epilepsy, developmental issues, and 3-methylglutaconic aciduria with next-generation sequencing. RESULTS: In each individual, we identified one of four different de novo monoallelic missense variants in CLPB. We show that these variants disturb refoldase and to a lesser extent ATPase activity of CLPB in a dominant-negative manner. Complexome profiling in fibroblasts showed CLPB at very high molecular mass comigrating with the prohibitins. In control fibroblasts, HAX1 migrated predominantly as monomer while in patient samples multiple HAX1 peaks were observed at higher molecular masses comigrating with CLPB thus suggesting a longer-lasting interaction between CLPB and HAX1. CONCLUSION: Both biallelic as well as specific monoallelic CLPB variants result in a phenotypic spectrum centered around neurodevelopmental delay, seizures, and neutropenia presumably mediated via HAX1.
AU  - Wortmann, S.B.*
AU  - Zietkiewicz, S.*
AU  - Guerrero-Castillo, S.*
AU  - Feichtinger, R.G.*
AU  - Wagner, M.
AU  - Russell, J.*
AU  - Ellaway, C.*
AU  - Mróz, D.*
AU  - Wyszkowski, H.*
AU  - Weis, D.*
AU  - Hannibal, I.*
AU  - von Stülpnagel, C.*
AU  - Cabrera-Orefice, A.*
AU  - Lichter-Konecki, U.*
AU  - Gaesser, J.*
AU  - Windreich, R.*
AU  - Myers, K.C.*
AU  - Lorsbach, R.*
AU  - Dale, R.C.*
AU  - Gersting, S.*
AU  - Prada, C.E.*
AU  - Christodoulou, J.*
AU  - Wolf, N.I.*
AU  - Venselaar, H.*
AU  - Mayr, J.A.*
AU  - Wevers, R.A.*
C1  - 62326
C2  - 50785
CY  - Campus, 4 Crinan St, London, N1 9xw, England
SP  - 1705-1714
TI  - Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.
JO  - Genet. Med.
VL  - 23
IS  - 9
PB  - Springernature
PY  - 2021
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - Unfortunately the funding information was not given. Funding is as follows: This work was funded by the ERA PerMed project PerMiM (Austrian Science Fund FWF, I4704-B) to S.B.W. This study was supported by a “Sonata Bis 5” grant of the National Science Center Poland (2015/18/E/NZ1/00673) to S.Z. and D.M.
AU  - Wortmann, S.B.*
AU  - Zietkiewicz, S.*
AU  - Guerrero-Castillo, S.*
AU  - Feichtinger, R.G.*
AU  - Wagner, M.
AU  - Russell, J.*
AU  - Ellaway, C.*
AU  - Mróz, D.*
AU  - Wyszkowski, H.*
AU  - Weis, D.*
AU  - Hannibal, I.*
AU  - von Stülpnagel, C.*
AU  - Cabrera-Orefice, A.*
AU  - Lichter-Konecki, U.*
AU  - Gaesser, J.*
AU  - Windreich, R.*
AU  - Myers, K.C.*
AU  - Lorsbach, R.*
AU  - Dale, R.C.*
AU  - Gersting, S.*
AU  - Prada, C.E.*
AU  - Christodoulou, J.*
AU  - Wolf, N.I.*
AU  - Venselaar, H.*
AU  - Mayr, J.A.*
AU  - Wevers, R.A.*
C1  - 62638
C2  - 50925
TI  - Correction to: Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.
JO  - Genet. Med.
PY  - 2021
SN  - 1530-0366
ER  - 

TY  - JOUR
AU  - Baertling, F.*
AU  - Wagner, M.
AU  - Brunet, T.*
AU  - Sabir, H.*
AU  - Wieczorek, D.*
AU  - Meitinger, T.
AU  - Meissner, T.*
AU  - Distelmaier, F.*
C1  - 57174
C2  - 47591
CY  - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa
SP  - 654-655
TI  - Fatal metabolic decompensation in carbonic anhydrase VA deficiency despite early treatment and control of hyperammonemia.
JO  - Genet. Med.
VL  - 22
IS  - 3
PB  - Nature Publishing Group
PY  - 2020
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - Purpose: This study aimsed to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals. Methods: Individuals harboring heterozygous missense or loss-of-function variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms, and literature review. For each individual, detailed phenotyping, classification, and structural modeling of the identified variant were performed. Results: The cohort comprises 23 individuals with pathogenic or likely pathogenic de novo variants in SNAP25. Intellectual disability and early-onset epilepsy were identified as the core symptoms of SNAP25-DEE, with recurrent findings of movement disorders, cerebral visual impairment, and brain atrophy. Structural modeling for all variants predicted possible functional defects concerning SNAP25 or impaired interaction with other components of the SNARE complex. Conclusion: We provide a comprehensive description of SNAP25-DEE with intellectual disability and early-onset epilepsy mostly occurring before the age of two years. These core symptoms and additional recurrent phenotypes show an overlap to genes encoding other components or associated proteins of the SNARE complex such as STX1B, STXBP1, or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed “SNAREopathies.”.
AU  - Klöckner, C.*
AU  - Sticht, H.*
AU  - Zacher, P.*
AU  - Popp, B.*
AU  - Babcock, H.E.*
AU  - Bakker, D.P.*
AU  - Barwick, K.*
AU  - Bonfert, M.V.*
AU  - Bönnemann, C.G.*
AU  - Brilstra, E.H.*
AU  - Chung, W.K.*
AU  - Clarke, A.J.*
AU  - Devine, P.*
AU  - Donkervoort, S.*
AU  - Fraser, J.L.*
AU  - Friedman, J.*
AU  - Gates, A.*
AU  - Ghoumid, J.*
AU  - Hobson, E.*
AU  - Horvath, G.*
AU  - Keller-Ramey, J.*
AU  - Keren, B.*
AU  - Kurian, M.A.*
AU  - Lee, V.*
AU  - Leppig, K.A.*
AU  - Lundgren, J.*
AU  - McDonald, M.T.*
AU  - McTague, A.*
AU  - Mefford, H.C.*
AU  - Mignot, C.*
AU  - Mikati, M.A.*
AU  - Nava, C.*
AU  - Raymond, F.L.*
AU  - Sampson, J.R.*
AU  - Sanchis-Juan, A.*
AU  - Shashi, V.*
AU  - Shieh, J.T.C.*
AU  - Shinawi, M.*
AU  - Slavotinek, A.*
AU  - Stödberg, T.*
AU  - Stong, N.*
AU  - Sullivan, J.A.*
AU  - Taylor, A.C.*
AU  - Toler, T.L.*
AU  - van den Boogaard, M.J.*
AU  - van der Crabben, S.N.*
AU  - van Gassen, K.L.I.*
AU  - van Jaarsveld, R.H.*
AU  - Van Ziffle, J.*
AU  - Wadley, A.F.*
AU  - Wagner, M.
AU  - Wigby, K.*
AU  - Wortmann, S.B.*
AU  - Zarate, Y.A.*
AU  - Møller, R.S.*
AU  - Lemke, J.R.*
AU  - Platzer, K.*
C1  - 60808
C2  - 49597
CY  - Campus, 4 Crinan St, London, N1 9xw, England
TI  - De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy.
JO  - Genet. Med.
PB  - Springernature
PY  - 2020
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - Purpose Biallelic variants inLARS1, coding for the cytosolic leucyl-tRNA synthetase, cause infantile liver failure syndrome 1 (ILFS1). Since its description in 2012, there has been no systematic analysis of the clinical spectrum and genetic findings. Methods Individuals with biallelic variants inLARS1were included through an international, multicenter collaboration including novel and previously published patients. Clinical variables were analyzed and functional studies were performed in patient-derived fibroblasts. Results Twenty-five individuals from 15 families were ascertained including 12 novel patients with eight previously unreported variants. The most prominent clinical findings are recurrent elevation of liver transaminases up to liver failure and encephalopathic episodes, both triggered by febrile illness. Magnetic resonance image (MRI) changes during an encephalopathic episode can be consistent with metabolic stroke. Furthermore, growth retardation, microcytic anemia, neurodevelopmental delay, muscular hypotonia, and infection-related seizures are prevalent. Aminoacylation activity is significantly decreased in all patient cells studied upon temperature elevation in vitro. Conclusion ILFS1 is characterized by recurrent elevation of liver transaminases up to liver failure in conjunction with abnormalities of growth, blood, nervous system, and musculature. Encephalopathic episodes with seizures can occur independently from liver crises and may present with metabolic stroke.
AU  - Lenz, D.*
AU  - Smith, D.E.C.*
AU  - Crushell, E.*
AU  - Husain, R.A.*
AU  - Salomons, G.S.*
AU  - Alhaddad, B.*
AU  - Bernstein, J.A.*
AU  - Bianzano, A.*
AU  - Biskup, S.*
AU  - Brennenstuhl, H.*
AU  - Caldari, D.*
AU  - Dikow, N.*
AU  - Haack, T.B.*
AU  - Hanson-Kahn, A.*
AU  - Harting, I.*
AU  - Horn, D.*
AU  - Hughes, J.*
AU  - Huijberts, M.*
AU  - Isidor, B.*
AU  - Kathemann, S.*
AU  - Kopajtich, R.
AU  - Kotzaeridou, U.*
AU  - Küry, S.*
AU  - Lainka, E.*
AU  - Laugwitz, L.*
AU  - Lupski, J.R.*
AU  - Posey, J.E.*
AU  - Reynolds, C.*
AU  - Rosenfeld, J.A.*
AU  - Schröter, J.*
AU  - Vansenne, F.*
AU  - Wagner, M.
AU  - Weiß, C.*
AU  - Wolffenbuttel, B.H.R.*
AU  - Wortmann, S.B.
AU  - Kölker, S.*
AU  - Hoffmann, G.F.*
AU  - Prokisch, H.
AU  - Mendes, M.I.*
AU  - Staufner, C.*
C1  - 59757
C2  - 49044
CY  - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa
SP  - 1863-1873
TI  - Genotypic diversity and phenotypic spectrum of infantile liver failure syndrome type 1 due to variants in LARS1.
JO  - Genet. Med.
VL  - 22
IS  - 11
PB  - Nature Publishing Group
PY  - 2020
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - Purpose: This study characterizes the clinical and genetic features of nine unrelated patients with de novo variants in the NR4A2 gene. Methods: Variants were identified and de novo origins were confirmed through trio exome sequencing in all but one patient. Targeted RNA sequencing was performed for one variant to confirm its splicing effect. Independent discoveries were shared through GeneMatcher. Results: Missense and loss-of-function variants in NR4A2 were identified in patients from eight unrelated families. One patient carried a larger deletion including adjacent genes. The cases presented with developmental delay, hypotonia (six cases), and epilepsy (six cases). De novo status was confirmed for eight patients. One variant was demonstrated to affect splicing and result in expression of abnormal transcripts likely subject to nonsense-mediated decay. Conclusion: Our study underscores the importance of NR4A2 as a disease gene for neurodevelopmental disorders and epilepsy. The identified variants are likely causative of the seizures and additional developmental phenotypes in these patients.
AU  - Singh, S.*
AU  - Gupta, A.*
AU  - Zech, M.
AU  - Sigafoos, A.N.*
AU  - Clark, K.J.*
AU  - Dincer, Y.*
AU  - Wagner, M.
AU  - Humberson, J.B.*
AU  - Green, S.*
AU  - van Gassen, K.*
AU  - Brandt, T.*
AU  - Schnur, R.E.*
AU  - Millan, F.*
AU  - Si, Y.*
AU  - Mall, V.*
AU  - Winkelmann, J.
AU  - Gavrilova, R.H.*
AU  - Klee, E.W.*
AU  - Engleman, K.*
AU  - Safina, N.P.*
AU  - Slaugh, R.*
AU  - Bryant, E.M.*
AU  - Tan, W.H.*
AU  - Granadillo, J.*
AU  - Misra, S.N.*
AU  - Schaefer, G.B.*
AU  - Towner, S.*
AU  - Brilstra, E.H.*
AU  - Koeleman, B.P.C.*
C1  - 59025
C2  - 48545
CY  - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa
SP  - 1413–1417
TI  - De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy.
JO  - Genet. Med.
VL  - 22
PB  - Nature Publishing Group
PY  - 2020
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - Purpose Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis. Methods Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods. Results One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the beta-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: beta-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger-Huet anomaly/SOPH). Conclusion We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.
AU  - Staufner, C.*
AU  - Peters, B.*
AU  - Wagner, M.
AU  - Alameer, S.*
AU  - Barić, I.*
AU  - Broué, P.*
AU  - Bulut, D.*
AU  - Church, J.A.*
AU  - Crushell, E.*
AU  - Dalgıç, B.*
AU  - Das, A.M.*
AU  - Dick, A.*
AU  - Dikow, N.*
AU  - Dionisi-Vici, C.*
AU  - Distelmaier, F.*
AU  - Bozbulut, N.E.*
AU  - Feillet, F.*
AU  - Gonzales, E.*
AU  - Hadzic, N.*
AU  - Hauck, F.*
AU  - Hegarty, R.*
AU  - Hempel, M.*
AU  - Herget, T.*
AU  - Klein, C.*
AU  - Konstantopoulou, V.*
AU  - Kopajtich, R.
AU  - Kuster, A.*
AU  - Laass, M.W.*
AU  - Lainka, E.*
AU  - Larson-Nath, C.*
AU  - Leibner, A.*
AU  - Lurz, E.*
AU  - Mayr, J.A.*
AU  - McKiernan, P.J.*
AU  - Mention, K.*
AU  - Moog, U.*
AU  - Mungan, N.O.*
AU  - Riedhammer, K.M.
AU  - Santer, R.*
AU  - Palafoll, I.V.*
AU  - Vockley, J.*
AU  - Westphal, D.S.
AU  - Wiedemann, A.*
AU  - Wortmann, S.B.
AU  - Diwan, G.D.*
AU  - Russell, R.B.*
AU  - Prokisch, H.
AU  - Garbade, S.F.*
AU  - Kölker, S.*
AU  - Hoffmann, G.F.*
AU  - Lenz, D.*
C1  - 57419
C2  - 47787
CY  - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa
SP  - 610-621
TI  - Defining clinical subgroups and genotype-phenotype correlations in NBAS-associated disease across 110 patients.
JO  - Genet. Med.
VL  - 22
IS  - 3
PB  - Nature Publishing Group
PY  - 2020
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - Purpose Multiple acyl-CoA dehydrogenase deficiency (MADD) is a life-threatening, ultrarare inborn error of metabolism. Case reports described successful D,L-3-hydroxybutyrate (D,L-3-HB) treatment in severely affected MADD patients, but systematic data on efficacy and safety is lacking. Methods A systematic literature review and an international, retrospective cohort study on clinical presentation, D,L-3-HB treatment method, and outcome in MADD(-like) patients. Results Our study summarizes 23 MADD(-like) patients, including 14 new cases. Median age at clinical onset was two months (interquartile range [IQR]: 8 months). Median age at starting D,L-3-HB was seven months (IQR: 4.5 years). D,L-3-HB doses ranged between 100 and 2600 mg/kg/day. Clinical improvement was reported in 16 patients (70%) for cardiomyopathy, leukodystrophy, liver symptoms, muscle symptoms, and/or respiratory failure. D,L-3-HB appeared not effective for neuropathy. Survival appeared longer upon D,L-3-HB compared with historical controls. Median time until first clinical improvement was one month, and ranged up to six months. Reported side effects included abdominal pain, constipation, dehydration, diarrhea, and vomiting/nausea. Median D,L-3-HB treatment duration was two years (IQR: 6 years). D,L-3-HB treatment was discontinued in 12 patients (52%). Conclusion The strength of the current study is the international pooling of data demonstrating that D,L-3-HB treatment can be effective and safe in MADD(-like) patients.
AU  - van Rijt, W.J.*
AU  - Jager, E.A.*
AU  - Allersma, D.P.*
AU  - Aktuğlu Zeybek, A.C.*
AU  - Bhattacharya, K.*
AU  - Debray, F.G.*
AU  - Ellaway, C.J.*
AU  - Gautschi, M.*
AU  - Geraghty, M.T.*
AU  - Gil-Ortega, D.*
AU  - Larson, A.A.*
AU  - Moore, F.*
AU  - Morava, E.*
AU  - Morris, A.A.*
AU  - Oishi, K.*
AU  - Schiff, M.*
AU  - Scholl-Bürgi, S.*
AU  - Tchan, M.C.*
AU  - Vockley, J.*
AU  - Witters, P.*
AU  - Wortmann, S.B.
AU  - van Spronsen, F.*
AU  - van Hove, J.L.K.*
AU  - Derks, T.G.J.*
C1  - 57762
C2  - 48125
CY  - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa
SP  - 908–916
TI  - Efficacy and safety of D,L-3-hydroxybutyrate (D,L-3-HB) treatment in multiple acyl-CoA dehydrogenase deficiency.
JO  - Genet. Med.
VL  - 22
PB  - Nature Publishing Group
PY  - 2020
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - Purpose TNR, encoding Tenascin-R, is an extracellular matrix glycoprotein involved in neurite outgrowth and neural cell adhesion, proliferation and migration, axonal guidance, myelination, and synaptic plasticity. Tenascin-R is exclusively expressed in the central nervous system with highest expression after birth. The protein is crucial in the formation of perineuronal nets that ensheath interneurons. However, the role of Tenascin-R in human pathology is largely unknown. We aimed to establish TNR as a human disease gene and unravel the associated clinical spectrum. Methods Exome sequencing and an online matchmaking tool were used to identify patients with biallelic variants in TNR. Results We identified 13 individuals from 8 unrelated families with biallelic variants in TNR sharing a phenotype consisting of spastic para- or tetraparesis, axial muscular hypotonia, developmental delay, and transient opisthotonus. Four homozygous loss-of-function and four different missense variants were identified. Conclusion We establish TNR as a disease gene for an autosomal recessive nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus and highlight the role of central nervous system extracellular matrix proteins in the pathogenicity of spastic disorders.
AU  - Wagner, M.
AU  - Lévy, J.*
AU  - Jung-Klawitter, S.*
AU  - Bakhtiari, S.*
AU  - Monteiro, F.*
AU  - Maroofian, R.*
AU  - Bierhals, T.*
AU  - Hempel, M.*
AU  - Elmaleh-Bergès, M.*
AU  - Kitajima, J.P.*
AU  - Kim, C.A.*
AU  - Salomao, J.G.*
AU  - Amor, D.J.*
AU  - Cooper, M.S.*
AU  - Perrin, L.*
AU  - Pipiras, E.*
AU  - Neu, A.*
AU  - Doosti, M.*
AU  - Karimiani, E.G.*
AU  - Toosi, M.B.*
AU  - Houlden, H.*
AU  - Jin, S.C.*
AU  - Si, Y.C.*
AU  - Rodan, L.H.*
AU  - Venselaar, H.*
AU  - Kruer, M.C.*
AU  - Kok, F.*
AU  - Hoffmann, G.F.*
AU  - Strom, T.M.*
AU  - Wortmann, S.B.
AU  - Tabet, A.C.*
AU  - Opladen, T.*
C1  - 58474
C2  - 48247
CY  - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa
SP  - 1061-1068
TI  - Loss of TNR causes a nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus.
JO  - Genet. Med.
VL  - 22
IS  - 6
PB  - Nature Publishing Group
PY  - 2020
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - Purpose: Skeletal muscle growth and regeneration rely on muscle stem cells, called satellite cells. Specific transcription factors, particularly PAX7, are key regulators of the function of these cells. Knockout of this factor in mice leads to poor postnatal survival; however, the consequences of a lack of PAX7 in humans have not been established. Methods: Here, we study five individuals with myopathy of variable severity from four unrelated consanguineous couples. Exome sequencing identified pathogenic variants in the PAX7 gene. Clinical examination, laboratory tests, and muscle biopsies were performed to characterize the disease. Results: The disease was characterized by hypotonia, ptosis, muscular atrophy, scoliosis, and mildly dysmorphic facial features. The disease spectrum ranged from mild to severe and appears to be progressive. Muscle biopsies showed the presence of atrophic fibers and fibroadipose tissue replacement, with the absence of myofiber necrosis. A lack of PAX7 expression was associated with satellite cell pool exhaustion; however, the presence of residual myoblasts together with regenerating myofibers suggest that a population of PAX7-independent myogenic cells partially contributes to muscle regeneration. Conclusion: These findings show that biallelic variants in the master transcription factor PAX7 cause a new type of myopathy that specifically affects satellite cell survival.
AU  - Feichtinger, R.G.*
AU  - Mucha, B.E.*
AU  - Hengel, H.*
AU  - Orfi, Z.*
AU  - Makowski, C.*
AU  - Dort, J.*
AU  - D'Anjou, G.*
AU  - Nguyen, T.T.M.*
AU  - Buchert, R.*
AU  - Juenger, H.*
AU  - Freisinger, P.*
AU  - Baumeister, S.*
AU  - Schoser, B.*
AU  - Ahting, U.*
AU  - Keimer, R.*
AU  - Nguyen, C.E.*
AU  - Fabre, P.*
AU  - Gauthier, J.*
AU  - Miguet, M.*
AU  - Lopes, F.*
AU  - AlHakeem, A.*
AU  - Alhashem, A.*
AU  - Tabarki, B.*
AU  - Kandaswamy, K.K.*
AU  - Bauer, P.*
AU  - Steinbacher, P.*
AU  - Prokisch, H.
AU  - Sturm, M.*
AU  - Strom, T.M.
AU  - Ellezam, B.*
AU  - Mayr, J.A.*
AU  - Schöls, L.*
AU  - Michaud, J.L.*
AU  - Campeau, P.M.*
AU  - Haack, T.B.*
AU  - Dumont, N.A.*
C1  - 56080
C2  - 46803
SP  - 2521-2531
TI  - Biallelic variants in the transcription factor PAX7 are a new genetic cause of myopathy.
JO  - Genet. Med.
VL  - 21
IS  - 11
PY  - 2019
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - Purpose: Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal Factin polymerization and dysregulated protein recycling.Methods: We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency.Results: The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies, feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination.Conclusion: The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.
AU  - Fountain, M.D.*
AU  - Oleson, D.S.*
AU  - Rech, M.E.*
AU  - Segebrecht, L.*
AU  - Hunter, J.V.*
AU  - McCarthy, J.M.*
AU  - Lupo, P.J.*
AU  - Holtgrewe, M.*
AU  - Moran, R.*
AU  - Rosenfeld, J.A.*
AU  - Isidor, B.*
AU  - Le Caignec, C.*
AU  - Saenz, M.S.*
AU  - Pedersen, R.C.*
AU  - Morgan, T.M.*
AU  - Pfotenhauer, J.P.*
AU  - Xia, F.*
AU  - Bi, W.*
AU  - Kang, S.H.L.*
AU  - Patel, A.*
AU  - Krantz, I.D.*
AU  - Raible, S.E.*
AU  - Smith, W.*
AU  - Cristian, I.*
AU  - Torti, E.*
AU  - Juusola, J.*
AU  - Millan, F.*
AU  - Wentzensen, I.M.*
AU  - Person, R.E.*
AU  - Küry, S.*
AU  - Bézieau, S.*
AU  - Uguen, K.*
AU  - Férec, C.*
AU  - Munnich, A.*
AU  - van Haelst, M.*
AU  - Lichtenbelt, K.D.*
AU  - van Gassen, K.*
AU  - Hagelstrom, T.*
AU  - Chawla, A.*
AU  - Perry, D.L.*
AU  - Taft, R.J.*
AU  - Jones, M.*
AU  - Masser-Frye, D.*
AU  - Dyment, D.*
AU  - Venkateswaran, S.*
AU  - Li, C.*
AU  - Escobar, L.F.*
AU  - Horn, D.*
AU  - Spillmann, R.C.*
AU  - Peña, L.*
AU  - Wierzba, J.*
AU  - Strom, T.M.
AU  - Parenti, I.*
AU  - Kaiser, F.J.*
AU  - Ehmke, N.*
AU  - Schaaf, C.P.*
C1  - 55425
C2  - 46345
CY  - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa
SP  - 1797-1807
TI  - Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies.
JO  - Genet. Med.
VL  - 21
IS  - 8
PB  - Nature Publishing Group
PY  - 2019
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - Purpose: The purpose of this study was to expand the genetic architecture of neurodevelopmental disorders, and to characterize the clinical features of a novel cohort of affected individuals with variants in ZNF142, a C 2 H 2 domain-containing transcription factor. Methods: Four independent research centers used exome sequencing to elucidate the genetic basis of neurodevelopmental phenotypes in four unrelated families. Following bioinformatic filtering, query of control data sets, and secondary variant confirmation, we aggregated findings using an online data sharing platform. We performed in-depth clinical phenotyping in all affected individuals. Results: We identified seven affected females in four pedigrees with likely pathogenic variants in ZNF142 that segregate with recessive disease. Affected cases in three families harbor either nonsense or frameshifting likely pathogenic variants predicted to undergo nonsense mediated decay. One additional trio bears ultrarare missense variants in conserved regions of ZNF142 that are predicted to be damaging to protein function. We performed clinical comparisons across our cohort and noted consistent presence of intellectual disability and speech impairment, with variable manifestation of seizures, tremor, and dystonia. Conclusion: Our aggregate data support a role for ZNF142 in nervous system development and add to the emergent list of zinc finger proteins that contribute to neurocognitive disorders.
AU  - Khan, K.*
AU  - Zech, M.
AU  - Morgan, A.T.*
AU  - Amor, D.J.*
AU  - Škorvánek, M.*
AU  - Khan, T.N.*
AU  - Hildebrand, M.S.*
AU  - Jackson, V.E.*
AU  - Scerri, T.S.*
AU  - Coleman, M.*
AU  - Rigbye, K.A.*
AU  - Scheffer, I.E.*
AU  - Bahlo, M.*
AU  - Wagner, M.
AU  - Lam, D.D.
AU  - Berutti, R.
AU  - Havránková, P.*
AU  - Fečíková, A.*
AU  - Strom, T.M.
AU  - Han, V.*
AU  - Dosekova, P.*
AU  - Gdovinova, Z.*
AU  - Laccone, F.*
AU  - Jameel, M.*
AU  - Mooney, M.R.*
AU  - Baig, S.M.*
AU  - Jech, R.*
AU  - Davis, E.E.*
AU  - Katsanis, N.*
AU  - Winkelmann, J.
C1  - 55959
C2  - 46709
SP  - 2532-2542
TI  - Recessive variants in ZNF142 cause a complex neurodevelopmental disorder with intellectual disability, speech impairment, seizures, and dystonia.
JO  - Genet. Med.
VL  - 21
IS  - 11
PY  - 2019
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - Purpose: Biallelic mutations in SCYL1 were recently identified as causing a syndromal disorder characterized by peripheral neuropathy, cerebellar atrophy, ataxia, and recurrent episodes of liver failure. The occurrence of SCYL1 deficiency among patients with previously undetermined infantile cholestasis or acute liver failure has not been studied; furthermore, little is known regarding the hepatic phenotype.Methods: We aimed to identify patients with SCYL1 variants within an exome-sequencing study of individuals with infantile cholestasis or acute liver failure of unknown etiology. Deep clinical and biochemical phenotyping plus analysis of liver biopsies and functional studies on fibroblasts were performed.Results: Seven patients from five families with biallelic SCYL1 variants were identified. The main clinical phenotype was recurrent low gamma-glutamyl-transferase (GGT) cholestasis or acute liver failure with onset in infancy and a variable neurological phenotype of later onset (CALFAN syndrome). Liver crises were triggered by febrile infections and were transient, but fibrosis developed. Functional studies emphasize that SCYL1 deficiency is linked to impaired intracellular trafficking.Conclusion: SCYL1 deficiency can cause recurrent low-GGT cholestatic liver dysfunction in conjunction with a variable neurological phenotype. Like NBAS deficiency, it is a member of the emerging group of congenital disorders of intracellular trafficking causing hepatopathy.
AU  - Lenz, D.*
AU  - McClean, P.*
AU  - Kansu, A.*
AU  - Bonnen, P.E.*
AU  - Ranucci, G.*
AU  - Thiel, C.*
AU  - Straub, B.K.*
AU  - Harting, I.*
AU  - Alhaddad, B.*
AU  - Dimitrov, B.*
AU  - Kotzaeridou, U.*
AU  - Wenning, D.*
AU  - Iorio, R.*
AU  - Himes, R.W.*
AU  - Kuloglu, Z.*
AU  - Blakely, E.L.*
AU  - Taylor, R.W.*
AU  - Meitinger, T.
AU  - Koelker, S.*
AU  - Prokisch, H.
AU  - Hoffmann, G.F.*
AU  - Haack, T.B.
AU  - Staufner, C.*
C1  - 54749
C2  - 45792
CY  - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa
SP  - 1255-1265
TI  - SCYL1 variants cause a syndrome with low gamma-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN).
JO  - Genet. Med.
VL  - 20
IS  - 10
PB  - Nature Publishing Group
PY  - 2018
SN  - 1530-0366
ER  - 

TY  - JOUR
AB  - Purpose:Lynch syndrome (LS) screening among patients with newly diagnosed colorectal cancer can decrease mortality in their affected first-degree relatives. In Germany, it is not yet clinical practice and the cost-effectiveness of different testing strategies is unknown.Methods:We developed a decision-analytic model to analyze the cost-effectiveness of LS screening from the perspective of the German Statutory Health Insurance system. A total of 22 testing strategies considering family-history assessment, analysis of tumor samples (i.e., immunohistochemistry (IHC), microsatellite instability, and BRAF mutation testing) and genetic sequencing were analyzed. Life-years gained in relatives by closed-meshed colonoscopy and aspirin prophylaxis were estimated by Markov models. Uncertainty was assessed deterministically and probabilistically.Results:On average, detected mutation carriers gained 0.52 life-years (undiscounted: 1.34) by increased prevention. Most strategies were dominated, with three exceptions: family assessment by the Bethesda criteria followed by IHC and BRAF testing and genetic sequencing; IHC and BRAF testing and genetic sequencing; and direct sequencing of all index patients. Their incremental cost-effectiveness was [euro ]77,268, [euro ]253,258, and [euro ]4,188,036 per life-year gained, respectively.Conclusion:The results were less favorable than those of previous models. Chemoprevention appears to provide comparably low additional benefit and improves cost-effectiveness only slightly.
AU  - Severin, F.
AU  - Stollenwerk, B.
AU  - Holinski-Feder, E.*
AU  - Meyer, E.
AU  - Heinemann, V.*
AU  - Giessen-Jung, C.*
AU  - Rogowski, W.H.
C1  - 43072
C2  - 35996
SP  - 765-773
TI  - Economic evaluation of genetic screening for Lynch syndrome in Germany.
JO  - Genet. Med.
VL  - 17
IS  - 10
PY  - 2015
SN  - 1530-0366
ER  -