TY  - JOUR
AB  - Plasma membrane calcium ATPases (PMCAs) encoded by ATP2B genes have been implicated in Mendelian diseases with ataxia, dystonia, and intellectual disability. Work to date has shown that ATP2B2 (encoding PMCA2) is required for synaptic function and Purkinje-cell integrity in the cerebellum. A recent case series has linked ATP2B2 to a novel entity, characterized by neurodevelopmental and movement phenotypes, in only seven individuals. We called for collaboration to collect five unpublished families affected by the new rare ATP2B2-related condition. Exome-/genome sequencing-identified genotypes included four likely pathogenic/pathogenic heterozygous de novo missense variants and one dominantly inherited end-truncating frameshift allele. The six affected individuals shared features with the described patients including developmental delay, cognitive disturbances, epilepsy, autistic traits, and motor disorders. Striking cerebellar atrophy was observed in one affected individual. In association with hearing loss and movement abnormalities, we report a recurrent p.(Glu457Lys) substitution, previously documented in a neurologically impaired ATP2B2 mouse mutant. Our study further delineates the mutational spectrum and presentation of a human syndrome caused by ATP2B2 variants, confirming the importance of PMCA2 in neurotypical and cerebellar development.
AU  - Stehr, A.M.*
AU  - Lenberg, J.*
AU  - Friedman, J.*
AU  - Dobbelaere, D.*
AU  - Imbard, A.*
AU  - Lévy, J.*
AU  - Donoghue, S.*
AU  - Derive, N.*
AU  - Stoeva, R.*
AU  - Gueguen, P.*
AU  - Zech, M.
C1  - 71931
C2  - 56536
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Consolidating the role of mutated ATP2B2 in neurodevelopmental and cerebellar pathologies.
JO  - Clin. Genet.
PB  - Wiley
PY  - 2024
SN  - 0009-9163
ER  - 

TY  - JOUR
AB  - NSD2 dimethylates histone H3 at lysine 36 (H3K36me2) and is located in the Wolf-Hirschhorn syndrome (WHS) critical region. Recent descriptions have delineated loss-of-function (LoF) variants in NSD2 with a distinct disorder. The oncogenic missense variant p.Glu1099Lys occurs somatically in leukemia and has a gain-of-function (GoF) effect. We describe two individuals carrying p.Glu1099Lys as heterozygous de novo germline variant identified by exome sequencing (ES) of blood DNA and subsequently confirmed in two ectodermal tissues. Clinically, these individuals are characterized by intellectual disability, coarse/ square facial gestalt, abnormalities of the hands, and organomegaly. Public cell lines with NSD2 GoF variants had increased K36me2, DNA promoter methylation, and dysregulated RNA expression. NSD2 GoF caused by p.Glu1099Lys is associated with a novel phenotype different from WHS and Rauch-Steindl syndrome (RAUST).
AU  - Popp, B.*
AU  - Brugger, M.*
AU  - Poschmann, S.*
AU  - Bartolomaeus, T.*
AU  - Radtke, M.*
AU  - Hentschel, J.*
AU  - di Donato, N.*
AU  - Rump, A.*
AU  - Gburek-Augustat, J.*
AU  - Graf, E.*
AU  - Wagner, M.
AU  - Sorge, I.*
AU  - Lemke, J.R.*
AU  - Meitinger, T.*
AU  - Abou Jamra, R.*
AU  - Strehlow, V.*
AU  - Brunet, T.
C1  - 66362
C2  - 53149
SP  - 226-230
TI  - The constitutional gain-of-function variant p.Glu1099Lys in NSD2 is associated with a novel syndrome.
JO  - Clin. Genet.
VL  - 103
IS  - 2
PY  - 2023
SN  - 0009-9163
ER  - 

TY  - JOUR
AB  - Biallelic variants in the ACADM gene cause medium-chain acyl-CoA dehydrogenase deficiency (MCADD). This study reports on differences in the occurrence of secondary free carnitine (C0) deficiency and different biochemical phenotypes related to genotype and age in 109 MCADD patients followed-up at a single tertiary care center during 22 years. C0 deficiency occurred earlier and more frequently in c.985A>G homozygotes (genotype A) compared to c.985A>G compound heterozygotes (genotype B) and individuals carrying variants other than c.985A>G and c.199C>T (genotype D) (median age 4.2 vs. 6.6 years; p < 0.001). No patient carrying c.199C>T (genotype C) developed C0 deficiency. A daily dosage of 20-40 mg/kg carnitine was sufficient to maintain normal C0 concentrations. Compared to genotype A as reference group, octanoylcarnitine (C8) was significantly lower in genotypes B and C, whereas C0 was significantly higher by 8.28 μmol/l in genotype C (p < 0.05). In conclusion, C0 deficiency is mainly found in patients with pathogenic genotypes associated with high concentrations of presumably toxic acylcarnitines, while individuals carrying the variant c.199C>T are spared and show consistently mild biochemical phenotypes into adulthood. Low-dose carnitine supplementation maintains normal C0 concentrations. However, future studies need to evaluate clinical benefits on acute and chronic manifestations of MCADD. This article is protected by copyright. All rights reserved.
AU  - Weiss, K.J.*
AU  - Berger, U.*
AU  - Haider, M.*
AU  - Wagner, M.
AU  - Märtner, E.M.C.*
AU  - Regenauer-Vandewiele, S.*
AU  - Lotz-Havla, A.*
AU  - Schuhmann, E.*
AU  - Röschinger, W.*
AU  - Maier, E.M.*
C1  - 67520
C2  - 54084
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 644-654
TI  - Free carnitine concentrations and biochemical parameters in medium-chain acyl-CoA dehydrogenase deficiency: Genotype-phenotype correlation.
JO  - Clin. Genet.
VL  - 103
IS  - 6
PB  - Wiley
PY  - 2023
SN  - 0009-9163
ER  - 

TY  - JOUR
AB  - Biallelic variants of the gene encoding for the zinc-finger protein 142 (ZNF142) have recently been associated with intellectual disability (ID), speech impairment, seizures, and movement disorders in nine individuals from five families. In this study, we obtained phenotype and genotype information of 26 further individuals from 16 families. Among the 27 different ZNF142 variants identified in the total of 35 individuals only four were missense. Missense variants may give a milder phenotype by changing the local structure of ZF motifs as suggested by protein modeling; but this correlation should be validated in larger cohorts and pathogenicity of the missense variants should be investigated with functional studies. Clinical features of the 35 individuals suggest that biallelic ZNF142 variants lead to a syndromic neurodevelopmental disorder with mild to moderate ID, varying degrees of delay in language and gross motor development, early onset seizures, hypotonia, behavioral features, movement disorders, and facial dysmorphism. The differences in symptom frequencies observed in the unpublished individuals compared to those of published, and recognition of previously underemphasized facial features are likely to be due to the small sizes of the previous cohorts, which underlines the importance of larger cohorts for the phenotype descriptions of rare genetic disorders.
AU  - Christensen, M.B.*
AU  - Levy, A.M.*
AU  - Mohammadi, N.A.*
AU  - Niceta, M.*
AU  - Kaiyrzhanov, R.*
AU  - Dentici, M.L.*
AU  - Al Alam, C.*
AU  - Alesi, V.*
AU  - Benoit, V.*
AU  - Bhatia, K.P.*
AU  - Bierhals, T.*
AU  - Boßelmann, C.M.*
AU  - Buratti, J.*
AU  - Callewaert, B.*
AU  - Ceulemans, B.*
AU  - Charles, P.*
AU  - De Wachter, M.*
AU  - Dehghani, M.*
AU  - D'haenens, E.*
AU  - Doco-Fenzy, M.*
AU  - Geßner, M.*
AU  - Gobert, C.*
AU  - Guliyeva, U.*
AU  - Haack, T.B.*
AU  - Hammer, T.B.*
AU  - Heinrich, T.*
AU  - Hempel, M.*
AU  - Herget, T.*
AU  - Hoffmann, U.*
AU  - Horvath, J.*
AU  - Houlden, H.*
AU  - Keren, B.*
AU  - Kresge, C.*
AU  - Kumps, C.*
AU  - Lederer, D.J.*
AU  - Lermine, A.*
AU  - Magrinelli, F.*
AU  - Maroofian, R.*
AU  - Vahidi Mehrjardi, M.Y.*
AU  - Moudi, M.*
AU  - Müller, A.J.*
AU  - Oostra, A.J.*
AU  - Pletcher, B.A.*
AU  - Ros-Pardo, D.*
AU  - Samarasekera, S.*
AU  - Tartaglia, M.*
AU  - Van Schil, K.*
AU  - Vogt, J.*
AU  - Wassmer, E.*
AU  - Winkelmann, J.
AU  - Zaki, M.S.*
AU  - Zech, M.
AU  - Lerche, H.*
AU  - Radio, F.C.*
AU  - Gómez-Puertas, P.*
AU  - Møller, R.S.*
AU  - Tümer, Z.*
C1  - 65388
C2  - 52374
SP  - 98-109
TI  - Biallelic variants in ZNF142 lead to a syndromic neurodevelopmental disorder.
JO  - Clin. Genet.
VL  - 102
IS  - 2
PY  - 2022
SN  - 0009-9163
ER  - 

TY  - JOUR
AB  - Up to 40% of neurodevelopmental disorders (NDDs) such as intellectual disability, developmental delay, autism spectrum disorder, and developmental motor abnormalities have a documented underlying monogenic defect, primarily due to de novo variants. Still, the overall burden of de novo variants as well as novel disease genes in NDDs await discovery. We performed parent-offspring trio exome sequencing in 231 individuals with NDDs. Phenotypes were compiled using human phenotype ontology terms. The overall diagnostic yield was 49.8% (n = 115/231) with de novo variants contributing to more than 80% (n = 93/115) of all solved cases. De novo variants affected 72 different-mostly constrained-genes. In addition, we identified putative pathogenic variants in 16 genes not linked to NDDs to date. Reanalysis performed in 80 initially unsolved cases revealed a definitive diagnosis in two additional cases. Our study consolidates the contribution and genetic heterogeneity of de novo variants in NDDs highlighting trio exome sequencing as effective diagnostic tool for NDDs. Besides, we illustrate the potential of a trio-approach for candidate gene discovery and the power of systematic reanalysis of unsolved cases.
AU  - Brunet, T.*
AU  - Jech, R.*
AU  - Brugger, M.*
AU  - Kovacs, R.*
AU  - Alhaddad, B.*
AU  - Leszinski, G.*
AU  - Riedhammer, K.M.*
AU  - Westphal, D.S.*
AU  - Mahle, I.*
AU  - Mayerhanser, K.*
AU  - Škorvánek, M.*
AU  - Weber, S.
AU  - Graf, E.
AU  - Berutti, R.*
AU  - Necpál, J.*
AU  - Havránková, P.*
AU  - Pavelekova, P.*
AU  - Hempel, M.*
AU  - Kotzaeridou, U.*
AU  - Hoffmann, G.F.*
AU  - Leiz, S.*
AU  - Makowski, C.*
AU  - Roser, T.*
AU  - Schroeder, S.A.*
AU  - Steinfeld, R.*
AU  - Strobl-Wildemann, G.*
AU  - Hoefele, J.*
AU  - Borggraefe, I.*
AU  - Distelmaier, F.*
AU  - Strom, T.M.*
AU  - Winkelmann, J.
AU  - Meitinger, T.*
AU  - Zech, M.
AU  - Wagner, M.
C1  - 61486
C2  - 50311
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 14-28
TI  - De novo variants in neurodevelopmental disorders-experiences from a tertiary care center.
JO  - Clin. Genet.
VL  - 100
IS  - 1
PB  - Wiley
PY  - 2021
SN  - 0009-9163
ER  - 

TY  - JOUR
AB  - Aminoacyl-tRNA synthetases (ARSs) catalyze the first step of protein biosynthesis (canonical function) and have additional (non-canonical) functions outside of translation. Bi-allelic pathogenic variants in genes encoding ARSs are associated with various recessive mitochondrial and multisystem disorders. We describe here a multisystem clinical phenotype based on bi-allelic mutations in the two genes (FARSA, FARSB) encoding distinct subunits for tetrameric cytosolic phenylalanyl-tRNA synthetase (FARS1). Interstitial lung disease with cholesterol pneumonitis on histology emerged as an early characteristic feature and significantly determined disease burden. Additional clinical characteristics of the patients included neurological findings, liver dysfunction, and connective tissue, muscular and vascular abnormalities. Structural modeling of newly identified missense mutations in the alpha subunit of FARS1, FARSA, showed exclusive mapping to the enzyme's conserved catalytic domain. Patient-derived mutant cells displayed compromised aminoacylation activity in two cases, while remaining unaffected in another. Collectively, these findings expand current knowledge about the human ARS disease spectrum and support a loss of canonical and non-canonical function in FARS1-associated recessive disease.
AU  - Schuch, L.A.*
AU  - Forstner, M.*
AU  - Rapp, C.K.*
AU  - Li, Y.*
AU  - Smith, D.E.C.*
AU  - Mendes, M.I.*
AU  - Delhommel, F.
AU  - Sattler, M.
AU  - Emiralioğlu, N.*
AU  - Taskiran, E.Z.*
AU  - Orhan, D.*
AU  - Kiper, N.*
AU  - Rohlfs, M.*
AU  - Jeske, T.*
AU  - Hastreiter, M.*
AU  - Gerstlauer, M.*
AU  - Torrent-Vernetta, A.*
AU  - Moreno-Galdó, A.*
AU  - Kammer, B.*
AU  - Brasch, F.*
AU  - Reu-Hofer, S.*
AU  - Griese, M.*
C1  - 61499
C2  - 50318
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 789-801
TI  - FARS1-related disorders caused by bi-allelic mutations in cytosolic phenylalanyl-tRNA synthetase genes: Look beyond the lungs!
JO  - Clin. Genet.
VL  - 99
IS  - 6
PB  - Wiley
PY  - 2021
SN  - 0009-9163
ER  - 

TY  - JOUR
AU  - Schwaibold, E.M.C.*
AU  - Brugger, M.*
AU  - Wagner, M.
C1  - 62623
C2  - 50964
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 489-490
TI  - A C-terminal BCOR nonsense variant in a male patient expands the phenotypic spectrum of BCOR-associated syndromic microphthalmia.
JO  - Clin. Genet.
VL  - 100
IS  - 4
PB  - Wiley
PY  - 2021
SN  - 0009-9163
ER  - 

TY  - JOUR
AB  - Neurological symptoms are frequent and often a leading feature of childhood-onset mitochondrial disorders (MD) but the exact incidence of MD in unselected neuropediatric patients is unknown. Their early detection is desirable due to a potentially rapid clinical decline and the availability of management options. In 491 children with neurological symptoms a comprehensive diagnostic work-up including exome sequencing was performed. The success rate in terms of a molecular genetic diagnosis within our cohort was 51%. Disease-causing variants in a mitochondria-associated gene were detected in 12% of solved cases. In order to facilitate the clinical identification of MDs within neuropediatric cohorts, we have created an easy-to-use bedside-tool, the MDC-NP. In our cohort, the MDC-NP predicted disease conditions related to MDs with a sensitivity of 0.83, and a specificity of 0.96.
AU  - van der Ven, A.T.*
AU  - Johannsen, J.*
AU  - Kortüm, F.*
AU  - Wagner, M.
AU  - Tsiakas, K.*
AU  - Bierhals, T.*
AU  - Lessel, D.*
AU  - Herget, T.*
AU  - Kloth, K.*
AU  - Lisfeld, J.*
AU  - Scholz, T.*
AU  - Obi, N.*
AU  - Wortmann, S.B.
AU  - Prokisch, H.
AU  - Kubisch, C.*
AU  - Denecke, J.*
AU  - Santer, R.*
AU  - Hempel, M.*
C1  - 62949
C2  - 51199
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Prevalence and clinical prediction of mitochondrial disorders in a large neuropediatric cohort.
JO  - Clin. Genet.
PB  - Wiley
PY  - 2021
SN  - 0009-9163
ER  - 

TY  - JOUR
AB  - The gamma-1 isoform of casein kinase 1, the protein encoded byCSNK1G1, is involved in the growth and morphogenesis of cells. This protein is expressed ubiquitously among many tissue types, including the brain, where it regulates the phosphorylation of N-methyl-D-aspartate receptors and plays a role in synaptic transmission. One prior individual with a de novo variant inCSNK1Gpresenting with severe developmental delay and early-onset epilepsy has been reported. Here we report an updated clinical history of this previously published case, as well as four additional individuals with de novo variants inCSNK1G1identified via microarray-based comparative genomic hybridization, exome, or genome sequencing. All individuals (n = 5) had developmental delay. At least three individuals had diagnoses of autism spectrum disorder. All participants were noted to have dysmorphic facial features, although the reported findings varied widely and therefore may not clearly be recognizable. None of the participants had additional major malformations. Taken together, our data suggest thatCSNK1G1may be a cause of syndromic developmental delay and possibly autism spectrum disorder.
AU  - Gold, N.B.*
AU  - Li, D.*
AU  - Chassevent, A.*
AU  - Kaiser, F.J.*
AU  - Parenti, I.*
AU  - Strom, T.M.
AU  - Ramos, F.J.*
AU  - Puisac, B.*
AU  - Pié, J.*
AU  - McWalter, K.*
AU  - Guillen Sacoto, M.J.*
AU  - Cui, H.*
AU  - Saadeh-Haddad, R.*
AU  - Smith-Hicks, C.*
AU  - Rodan, L.*
AU  - Blair, E.*
AU  - Bhoj, E.*
C1  - 60307
C2  - 49376
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 571-576
TI  - Heterozygous de novo variants in CSNK1G1 are associated with syndromic developmental delay and autism spectrum disorder.
JO  - Clin. Genet.
VL  - 98
IS  - 6
PB  - Wiley
PY  - 2020
SN  - 0009-9163
ER  - 

TY  - JOUR
AB  - Rare pathogenicEIF2S3missense and terminal deletion variants cause the X-linked intellectual disability (ID) syndrome MEHMO, or a milder phenotype including pancreatic dysfunction and hypopituitarism. We present two unrelated male patients who carry novelEIF2S3pathogenic missense variants (p.(Thr144Ile) and p.(Ile159Leu)) thereby broadening the limited genetic spectrum and underscoring clinically variable expressivity of MEHMO. While the affected male with p.(Thr144Ile) presented with severe motor delay, severe microcephaly, moderate ID, epileptic seizures responsive to treatments, hypogenitalism, central obesity, facial features, and diabetes, the affected male with p.(Ile159Leu) presented with moderate ID, mild motor delay, microcephaly, epileptic seizures resistant to treatment, central obesity, and mild facial features. Both variants are located in the highly conserved guanine nucleotide binding domain of theEIF2S3encoded eIF2 gamma subunit of the heterotrimeric translation initiation factor 2 (eIF2) complex. Further, we investigated both variants in a structural model and in yeast. The reduced growth rates and lowered fidelity of translation with increased initiation at non-AUG codons observed for both mutants in these studies strongly support pathogenicity of the variants.
AU  - Kotzaeridou, U.*
AU  - Young-Baird, S.K.*
AU  - Suckow, V.*
AU  - Thornburg, A.G.*
AU  - Wagner, M.
AU  - Harting, I.*
AU  - Christ, S.*
AU  - Strom, T.M.
AU  - Dever, T.E.*
AU  - Kalscheuer, V.M.*
C1  - 59917
C2  - 49117
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 507-514
TI  - Novel pathogenic EIF2S3 missense variants causing clinically variable MEHMO syndrome with impaired eIF2γ translational function, and literature review.
JO  - Clin. Genet.
VL  - 98
IS  - 5
PB  - Wiley
PY  - 2020
SN  - 0009-9163
ER  - 

TY  - JOUR
AB  - NGLY1 encodes the enzyme N-glycanase that is involved in the degradation of glycoproteins as part of the endoplasmatic reticulum-associated degradation pathway. Variants in this gene have been described to cause a multisystem disease characterized by neuromotor impairment, neuropathy, intellectual disability, and dysmorphic features. Here, we describe four patients with pathogenic variants in NGLY1. As the clinical features and laboratory results of the patients suggested a multisystem mitochondrial disease, a muscle biopsy had been performed. Biochemical analysis in muscle showed a strongly reduced ATP production rate in all patients, while individual OXPHOS enzyme activities varied from normal to reduced. No causative variants in any mitochondrial disease genes were found using mtDNA analysis and whole exome sequencing. In all four patients, variants in NGLY1 were identified, including two unreported variants (c.849T>G (p.(Cys283Trp)) and c.1067A>G (p.(Glu356Gly)). Western blot analysis of N-glycanase in muscle and fibroblasts showed a complete absence of N-glycanase. One patient showed a decreased basal and maximal oxygen consumption rates in fibroblasts. Mitochondrial morphofunction fibroblast analysis showed patient specific differences when compared to control cell lines. In conclusion, variants in NGLY1 affect mitochondrial energy metabolism which in turn might contribute to the clinical disease course.
AU  - Panneman, D.M.*
AU  - Wortmann, S.B.
AU  - Haaxma, C.A.*
AU  - van Hasselt, P.M.*
AU  - Wolf, N.I.*
AU  - Hendriks, Y.*
AU  - Küsters, B.*
AU  - van Emst-de Vries, S.*
AU  - van de Westerlo, E.*
AU  - Koopman, W.J.H.*
AU  - Wintjes, L.*
AU  - van den Brandt, F.*
AU  - de Vries, M.*
AU  - Lefeber, D.J.*
AU  - Smeitink, J.A.M.*
AU  - Rodenburg, R.J.*
C1  - 57877
C2  - 48166
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 556-566
TI  - Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction.
JO  - Clin. Genet.
VL  - 97
IS  - 4
PB  - Wiley
PY  - 2020
SN  - 0009-9163
ER  - 

TY  - JOUR
AB  - Congenital heart defects (CHDs) are the most common birth defect with 30%-40% being explained by genetic aberrations. With next generation sequencing becoming widely available, we sought to evaluate the clinical utility of exome sequencing (ES) in prenatally diagnosed CHD. We retrospectively analyzed the diagnostic yield as well as non-conclusive and incidental findings in 30 cases with prenatally diagnosed CHDs using ES, mostly as parent-child trios. A genetic diagnosis was established in 20% (6/30). Non-conclusive results were found in 13% (4/30) and incidental findings in 10% (3/30). There was a phenotypic discrepancy between reported prenatal and postnatal extracardiac findings in 40% (8/20). However, none of these additional, postnatal findings altered the genetic diagnosis. Herein, ES in prenatally diagnosed CHDs results in a comparably high diagnostic yield. There was a significant proportion of incidental findings and variants of unknown significance as well as potentially pathogenic variants in novel disease genes. Such findings can bedevil genetic counseling and decision making for pregnancy termination. Despite the small cohort size, our data serve as a first basis to evaluate the value of prenatal ES in CHD for further studies emerging in the near future.
AU  - Westphal, D.S.
AU  - Leszinski, G.*
AU  - Rieger-Fackeldey, E.*
AU  - Graf, E.
AU  - Weirich, G.*
AU  - Meitinger, T.
AU  - Ostermayer, E.*
AU  - Oberhoffer, R.*
AU  - Wagner, M.
C1  - 55684
C2  - 46511
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 582-589
TI  - Lessons from exome sequencing in prenatally diagnosed heart defects: A basis for prenatal testing.
JO  - Clin. Genet.
VL  - 95
IS  - 5
PB  - Wiley
PY  - 2019
SN  - 0009-9163
ER  - 

TY  - JOUR
AB  - MPV17 encodes a putative channel-forming protein of the inner mitochondrial membrane and is involved in mitochondrial deoxynucleotide homeostasis. MPV17 mutations were first reported in patients with Navajo neurohepatopathy, an autosomal recessive mitochondrial DNA depletion syndrome, characterized by early-onset liver failure, failure to thrive as well as central and peripheral neurological involvement. Recently, two patients with juvenile-onset peripheral sensorimotor neuropathy associated with an MVP17 c.122G>A (p.Arg41Gln) variant have been reported. Here, we describe five additional patients from two unrelated families with sensorimotor axonal neuropathy without hepatocerebral affection caused by homozygous MPV17 variants. Patients of the first family carried the known c.122G>A variant and affected individuals of the second family had a novel c.376-9T>G near-splice variant, which was shown to result in an in-frame deletion of 11 amino acids. This report provides further evidence that MPV17 mutations should be considered in patients with pure, non-syndromic axonal neuropathy.
AU  - Baumann, M.*
AU  - Schreiber, H.*
AU  - Schlotter-Weigel, B.*
AU  - Löscher, W.N.*
AU  - Stucka, R.*
AU  - Karall, D.*
AU  - Strom, T.M.
AU  - Bauer, P.*
AU  - Krabichler, B.*
AU  - Fauth, C.*
AU  - Glaeser, D.*
AU  - Senderek, J.*
C1  - 54485
C2  - 45630
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 182-186
TI  - MPV17 mutations in juvenile- and adult-onset axonal sensorimotor polyneuropathy.
JO  - Clin. Genet.
VL  - 95
IS  - 1
PB  - Wiley
PY  - 2018
SN  - 0009-9163
ER  - 

TY  - JOUR
AB  - Biallelic mutations in SLC25A46, encoding a modified solute transporter involved in mitochondrial dynamics, have been identified in a wide range of conditions such as hereditary motor and sensory neuropathy with optic atrophy type VIB (OMIM: *610826) and congenital lethal pontocerebellar hypoplasia (PCH). To date, 18 patients from 13 families have been reported, presenting with the key clinical features of optic atrophy, peripheral neuropathy, and cerebellar atrophy. The course of the disease was highly variable ranging from severe muscular hypotonia at birth and early death to first manifestations in late childhood and survival into the fifties. Here we report on 4 patients from 2 families diagnosed with PCH who died within the first month of life from respiratory insufficiency. Patients from 1 family had pathoanatomically proven spinal motor neuron degeneration (PCH1). Using exome sequencing, we identified biallelic disease-segregating loss-of-function mutations in SLC25A46 in both families. Our study adds to the definition of the SLC25A46-associated phenotypic spectrum that includes neonatal fatalities due to PCH as the severe extreme.
AU  - Braunisch, M.C.*
AU  - Gallwitz, H.*
AU  - Abicht, A.*
AU  - Diebold, I.*
AU  - Holinski-Feder, E.*
AU  - van Maldergem, L.*
AU  - Lammens, M.*
AU  - Kovács-Nagy, R.*
AU  - Alhaddad, B.*
AU  - Strom, T.M.
AU  - Meitinger, T.
AU  - Senderek, J.*
AU  - Rudnik-Schöneborn, S.*
AU  - Haack, T.B.
C1  - 52363
C2  - 43933
CY  - Hoboken
SP  - 255-265
TI  - Extension of the phenotype of biallelic loss-of-function mutations in SLC25A46 to the severe form of pontocerebellar hypoplasia type I.
JO  - Clin. Genet.
VL  - 93
IS  - 2
PB  - Wiley
PY  - 2017
SN  - 0009-9163
ER  - 

TY  - JOUR
AB  - Identification of this additional patient from a distant part of the originally described pedigree (Synofzik et al. 2014) confirms pathogenicity of DNAJC3 mutations. Hypothyroidism is a newly identified feature in addition to the known phenotype (diabetes with multisystemic neurodegeneration).
AU  - Bublitz, S.K.*
AU  - Alhaddad, B.*
AU  - Synofzik, M.*
AU  - Kuhl, V.*
AU  - Lindner, A.*
AU  - Freiberg, C.*
AU  - Schmidt, H.*
AU  - Strom, T.M.
AU  - Haack, T.B.*
AU  - Deschauer, M.*
C1  - 51962
C2  - 43621
CY  - Hoboken
SP  - 561-562
TI  - Expanding the phenotype of DNAJC3 mutations: A case with hypothyroidism additionally to diabetes mellitus and multisystemic neurodegeneration.
JO  - Clin. Genet.
VL  - 92
IS  - 5
PB  - Wiley
PY  - 2017
SN  - 0009-9163
ER  - 

TY  - JOUR
AB  - Parkinson's disease (PD) is a genetically heterogeneous disorder and new putative disease genes are discovered constantly. Therefore, whole-exome sequencing could be an efficient approach to genetic testing in PD. To evaluate its performance in early-onset sporadic PD, we performed diagnostic exome sequencing in 80 individuals with manifestation of PD symptoms at age 40 or earlier and a negative family history of PD. Variants in validated and candidate disease genes and risk factors for PD and atypical Parkinson syndromes were annotated, followed by further analysis for selected variants. We detected pathogenic variants in Mendelian genes in 6.25% of cases and high-impact risk factor variants in GBA in 5% of cases, resulting in overall maximum diagnostic yield of 11.25%. One individual was compound heterozygous for variants affecting canonical splice sites in VPS13C, confirming the causal role of protein-truncating variants in this gene linked to autosomal-recessive early-onset PD. Despite the low diagnostic yield of exome sequencing in sporadic early-onset PD, the confirmation of the recently discovered VPS13C gene highlights its advantage over using predefined gene panels.
AU  - Schormair, B.
AU  - Kemlink, D.*
AU  - Mollenhauer, B.*
AU  - Fiala, O.*
AU  - Machetanz, G.*
AU  - Roth, J.*
AU  - Berutti, R.
AU  - Strom, T.M.
AU  - Haslinger, B.*
AU  - Trenkwalder, C.*
AU  - Zahorakova, D.*
AU  - Martasek, P.*
AU  - Ruzicka, E.*
AU  - Winkelmann, J.
C1  - 51787
C2  - 43517
CY  - Hoboken
SP  - 603-612
TI  - Diagnostic exome sequencing in early-onset Parkinson's disease confirms VPS13C as a rare cause of autosomal-recessive Parkinson's disease.
JO  - Clin. Genet.
VL  - 93
IS  - 3
PB  - Wiley
PY  - 2017
SN  - 0009-9163
ER  - 

TY  - JOUR
AB  - Spondyloocular syndrome (SOS) is a rare autosomal recessive, skeletal disorder. Two recent studies have shown that it is the result of biallelic sequence variants in the XYLT2 gene with pleiotropic effects in multiple organs, including retina, heart muscle, inner ear, cartilage, and bone. The XYLT2 gene encodes xylosyltransferase 2, which catalyzes the transfer of xylose (monosaccharide) to the core protein of proteoglycans (PGs) leading to initiating the process of PG assembly. SOS was originally characterized in 2 families A and B of Iraqi and Turkish origin, respectively. Using DNA from affected members of the same 2 families, we performed whole exome sequencing, which revealed 2 novel homozygous missense variants (c.1159C>T, p.Arg387Trp) and (c.2548G>C, p.Asp850His). Our findings extend the body of evidence that SOS is caused by homozygous variants in the XYLT2 gene. In addition, this report has extended the phenotypic description of SOS by adding follow-up data from 5 affected individuals in one of the two families, presented here.
AU  - Umair, M.
AU  - Eckstein, G.N.
AU  - Rudolph, G.*
AU  - Strom, T.M.
AU  - Graf, E.
AU  - Hendig, D.*
AU  - Hoover, J.*
AU  - Alanay, J.*
AU  - Meitinger, T.
AU  - Schmidt, H.*
AU  - Ahmad, W.*
C1  - 52334
C2  - 43914
CY  - Hoboken
SP  - 913-918
TI  - Homozygous XYLT2 variants as a cause of spondyloocular syndrome.
JO  - Clin. Genet.
VL  - 93
IS  - 4
PB  - Wiley
PY  - 2017
SN  - 0009-9163
ER  - 

TY  - JOUR
AB  - Cornelia de Lange syndrome (CdLS) is a clinically heterogeneous disorder characterized by typical facial dysmorphism, cognitive impairment and multiple congenital anomalies. Approximately 75% of patients carry a variant in one of the five cohesin-related genes NIPBL, SMC1A, SMC3, RAD21 and HDAC8. Herein we report on the clinical and molecular characterization of eleven patients carrying ten distinct variants in HDAC8. Given the high number of variants identified so far, we advise sequencing of HDAC8 as an indispensable part of the routine molecular diagnostic for patients with CdLS or CdLS-overlapping features. The phenotype of our patients is very broad whereas males tend to be more severely affected than females, who instead often present with less canonical CdLS features. The extensive clinical variability observed in the heterozygous females might be at least partially associated with a completely skewed X-inactivation, observed in seven out of eight female patients. Our cohort also includes two affected siblings whose unaffected mother was found to be mosaic for the causative mutation inherited to both affected children. This further supports the urgent need for an integration of highly sensitive sequencing technology to allow an appropriate molecular diagnostic, genetic counselling and risk prediction.
AU  - Parenti, I.*
AU  - Gervasini, C.*
AU  - Pozojevic, J.*
AU  - Wendt, K.S.*
AU  - Watrin, E.*
AU  - Azzollini, J.*
AU  - Braunholz, D.*
AU  - Buiting, K.*
AU  - Cereda, A.*
AU  - Engels, H.*
AU  - Garavelli, L.*
AU  - Glazar, R.*
AU  - Graffmann, B.*
AU  - Larizza, L.*
AU  - Lüdecke, H.J.*
AU  - Mariani, M.*
AU  - Masciadri, M.*
AU  - Pié, J.*
AU  - Ramos, F.J.*
AU  - Russo, S.*
AU  - Selicorni, A.*
AU  - Stefanova, M.*
AU  - Strom, T.M.
AU  - Werner, R.*
AU  - Wierzba, J.*
AU  - Zampino, G.*
AU  - Gillessen-Kaesbach, G.*
AU  - Wieczorek, D.*
AU  - Kaiser, F.J.*
C1  - 47858
C2  - 39606
CY  - Hoboken
SP  - 564-573
TI  - Expanding the clinical spectrum of the "HDAC8-phenotype" - implications for molecular diagnostics, counselling and risk prediction.
JO  - Clin. Genet.
VL  - 89
IS  - 5
PB  - Wiley-blackwell
PY  - 2016
SN  - 0009-9163
ER  - 

TY  - JOUR
AU  - Baquero-Montoya, C.*
AU  - Gil-Rodríguez, M.C.*
AU  - Braunholz, D.*
AU  - Teresa-Rodrigo, M.E.*
AU  - Obieglo, C.*
AU  - Gener, B.*
AU  - Schwarzmayr, T.
AU  - Strom, T.M.
AU  - Gómez-Puertas, P.*
AU  - Puisac, B.*
AU  - Gillessen-Kaesbach, G.*
AU  - Musio, A.*
AU  - Ramos, F.J.*
AU  - Kaiser, F.J.*
AU  - Pié, J.*
C1  - 29336
C2  - 33710
SP  - 595-597
TI  - Somatic mosaicism in a Cornelia de Lange syndrome patient with NIPBL mutation identified by different next generation sequencing approaches.
JO  - Clin. Genet.
VL  - 86
IS  - 6
PY  - 2014
SN  - 0009-9163
ER  - 

TY  - JOUR
AU  - Elstner, M.*
AU  - Bettecken, T.
AU  - Wasner, M.*
AU  - Anneser, F.*
AU  - Dichgans, M.*
AU  - Meitinger, T.
AU  - Gasser, T.*
AU  - Klopstock, T.*
C1  - 1914
C2  - 23468
SP  - 179-182
TI  - Familial carpal tunnel syndrome: Further evidence for a genetic contribution.
JO  - Clin. Genet.
VL  - 69
PY  - 2006
SN  - 0009-9163
ER  -