TY - JOUR AB - Background: Definition of the individual genotypes that cause a Mendelian phenotype is of great importance both to clinical diagnostics and disease characterization. Heterozygous de novo gain-of-function missense variants in RARB are associated with syndromic microphthalmia 12 (MCOPS12), a developmental disorder characterized by eye malformations and variable involvement of other organs. A subset of patients were described with poorly delineated movement disorders. Additionally, RARB bi-allelic loss-of-function variants, inherited from asymptomatic heterozygous carrier parents, have been found in a recessive family with four MCOPS12-affected members. Patient/methods: We used trio whole-exome sequencing to explore the molecular basis of disease in an individual with congenital eye abnormality and movement disorder. All patients with reported RARB variants were reviewed. Results: We report on identification of a heterozygous de novo RARB nonsense variant in a girl with microphthalmia and progressive generalized dystonia. Public database entries indicate that the de novo variant is recurrently present in clinically affected subjects but a literature report has not yet been available. Conclusions: We provide the first detailed evidence for a role of dominant RARB truncating alterations in congenital eye-brain disease, expanding the spectrum of MCOPS12-associated mutations. Considered together with the published family with bi-allelic variants, the data suggest manifestation and non-manifestation of disease in relation to almost identical RARB loss-of-function variations, an apparent paradox that is seen in a growing number of human genetic conditions associated with both recessive and dominant inheritance patterns. AU - Trieschmann, G.* AU - Wilhelm, C.* AU - Berweck, S.* AU - Zech, M. C1 - 68447 C2 - 54690 CY - Radarweg 29, 1043 Nx Amsterdam, Netherlands TI - De novo retinoic acid receptor beta (RARB) variant associated with microphthalmia and dystonia. JO - Eur. J. Med. Genet. VL - 66 IS - 8 PB - Elsevier PY - 2023 SN - 1769-7212 ER - TY - JOUR AU - Harrer, P. AU - Leppmeier, V.* AU - Berger, A.* AU - Demund, S.* AU - Winkelmann, J. AU - Berweck, S.* AU - Zech, M. C1 - 66345 C2 - 53143 TI - A de novo BCL11B variant case manifesting with dystonic movement disorder regarding the article "BCL11B-related disorder in two canadian children: Expanding the clinical phenotype (Prasad et al., 2020).". JO - Eur. J. Med. Genet. VL - 65 IS - 11 PY - 2022 SN - 1769-7212 ER - TY - JOUR AB - Variants in CSDE1, a gene encoding a constrained RNA-binding protein, have recently been associated with a spectrum of neurodevelopmental conditions encompassing autism, seizures and ocular abnormalities. According to previously reported individuals, pathogenic variants in CSDE1 are typically associated with developmental delay and intellectual disability. Here, we report one individual with normal neurodevelopment and adult-onset neuropsychiatric features (i.e., acute psychosis) due to the novel de novo truncating variant c.2272C  >  T, p.(Gln758*) in CSDE1 (NM_001242891.1). Neuropsychological assessment confirmed deficits regarding verbal fluency, semantic memory, executive function and processing speed. Overall, our findings expand the phenotypic spectrum of CSDE1-related disorder towards the mild end. AU - Krenn, M.* AU - Kepa, S.* AU - Kasprian, G.* AU - Riedhammer, K.M.* AU - Wagner, M. AU - Goedl-Fleischhacker, U.* AU - Milenkovic, I.* C1 - 64067 C2 - 52053 TI - A de novo truncating variant in CSDE1 in an adult-onset neuropsychiatric phenotype without intellectual disability. JO - Eur. J. Med. Genet. VL - 65 IS - 3 PY - 2022 SN - 1769-7212 ER - TY - JOUR AB - Background: ECHS1 encodes the mitochondrial short chain enoyl CoA hydratase 1 (SCEH). Biallelic ECHS1 variants have been associated with Leigh-like presentations and milder phenotypes with paroxysmal exercise-induced dystonia.Patients/methods: We used exome sequencing to investigate molecular bases of paroxysmal and non-paroxysmal dystonia in three patients and performed functional studies in fibroblasts. Disease presentation and response upon dietary interventions were documented.Results: We identified compound heterozygous ECHS1 missense variants in all individuals; all of them harbouring an c.518C > T (p.Ala173Val) variant. SCEH activity was impaired in patients' fibroblasts, respiratory chain-, and pyruvate-dehydrogenase-complex activities were normal in one individual.Patient 1 presented from the age of 2.5 years on with paroxysmal opisthotonic posturing. Patient 2 had a first metabolic crisis at the age 20 months developing recurrent exercise-induced dystonic episodes. Disease history of patient 3 was unremarkable for neurological findings until he first presented at the age of 20 years with persistent dystonia. Ketogenic diet had beneficial effects in patient 1. Neither ketogenic nor low protein diets led to milder symptoms in patient 2. Patient 3 benefits from low protein diet with improvement of his torticollis.Conclusions: In line with literature, our findings corroborate that the pathogenic ECHS1 variant c.518C > T (p. Ala173Val) is associated with milder phenotypes characterized by paroxysmal and non-paroxysmal dystonia. Because of the potentially treatable defect, especially in milder affected patients, it is important to consider SCEH deficiency not only in patients with Leigh-like syndrome but also in patients with paroxysmal dystonia and normal neurological findings between episodes. AU - Illsinger, S.* AU - Korenke, G.C.* AU - Boesch, S.* AU - Nocker, M.* AU - Karall, D.* AU - Nuoffer, J.M.* AU - Laugwitz, L.* AU - Mayr, J.A.* AU - Scholl-Bürgi, S.* AU - Freisinger, P.* AU - Kowald, T.* AU - Kölker, S.* AU - Prokisch, H. AU - Haack, T.B.* C1 - 59983 C2 - 49157 CY - Radarweg 29, 1043 Nx Amsterdam, Netherlands TI - Paroxysmal and non-paroxysmal dystonia in 3 patients with biallelic ECHS1 variants: Expanding the neurological spectrum and therapeutic approaches. JO - Eur. J. Med. Genet. VL - 63 IS - 11 PB - Elsevier PY - 2020 SN - 1769-7212 ER - TY - JOUR AB - We describe two sporadic and two familial cases with loss-of-function variants in PRPS1, which is located on the X chromosome and encodes phosphoribosyl pyrophosphate synthetase 1 (PRS-1). We illustrate the clinical variability associated with decreased PRS-1 activity, ranging from mild isolated hearing loss to severe encephalopathy. One of the variants we identified has already been reported with a phenotype similar to our patient's, whereas the other three were unknown. The clinical and biochemical information we provide will hopefully contribute to gain insight into the correlation between genotype and phenotype of this rare condition, both in females and in males. Moreover, our observation of a new family in which hemizygous males display hearing loss without any neurological or ophthalmological symptoms prompts us to suggest analysing PRPS1 in cases of isolated hearing loss. Eventually, PRPS1 variants should be considered as a differential diagnosis of mitochondrial disorders. AU - Mercati, O.* AU - Abi Warde, M.T.* AU - Lina-Granade, G.* AU - Rio, M.* AU - Heide, S.* AU - de Lonlay, P.* AU - Ceballos-Picot, I.* AU - Robert, M.P.* AU - Couloigner, V.* AU - Beltrand, J.* AU - Boddaert, N.* AU - Rodriguez, D.* AU - Rubinato, E.* AU - Lapierre, J.M.* AU - Merlette, C.* AU - Sanquer, S.* AU - Rötig, A.* AU - Prokisch, H. AU - Lyonnet, S.* AU - Loundon, N.* AU - Kaplan, J.* AU - Bonnefont, J.P.* AU - Munnich, A.* AU - Besmond, C.* AU - Jonard, L.* AU - Marlin, S.* C1 - 59950 C2 - 49141 CY - Radarweg 29, 1043 Nx Amsterdam, Netherlands TI - PRPS1 loss-of-function variants, from isolated hearing loss to severe congenital encephalopathy: New cases and literature review. JO - Eur. J. Med. Genet. VL - 63 IS - 11 PB - Elsevier PY - 2020 SN - 1769-7212 ER - TY - JOUR AB - Ankyrin-G, encoded by ANK3, plays an important role in neurodevelopment and neuronal function. There are multiple isoforms of Ankyrin-G resulting in differential tissue expression and function. Heterozygous missense mutations in ANK3 have been associated with autism spectrum disorder. Further, in three siblings a homozygous frameshift mutation affecting only the longest isoform and a patient with a balanced translocation disrupting all isoforms were documented. The latter four patients were affected by a variable degree of intellectual disability, attention deficit hyperactivity disorder and autism. Here, we report on a boy with speech impairment, intellectual disability, autistic features, macrocephaly, macrosomia, chronic hunger and an altered sleeping pattern. By trio-whole-exome sequencing, we identified the first de novo nonsense mutation affecting all ANK3 transcripts. Thus, our data expand the phenotype of ANK3-associated diseases and suggest an isoform-based, phenotypic continuum between dominant and recessive ANK3-associated pathologies. AU - Kloth, K.* AU - Denecke, J.* AU - Hempel, M.* AU - Johannsen, J.* AU - Strom, T.M. AU - Kubisch, C.* AU - Lessel, D.* C1 - 51493 C2 - 43243 CY - Amsterdam SP - 494-498 TI - First de novo ANK3 nonsense mutation in a boy with intellectual disability, speech impairment and autistic features. JO - Eur. J. Med. Genet. VL - 60 IS - 9 PB - Elsevier Science Bv PY - 2017 SN - 1769-7212 ER - TY - JOUR AB - Cornelia de Lange syndrome (CdLS) is a dominantly inherited developmental disorder caused by mutations in genes that encode for either structural (SMC1A, SMC3, RAD21) or regulatory (NIPBL, HDAC8) subunits of the cohesin complex. NIPBL represents the major gene of the syndrome and heterozygous mutations can be identified in more than 65% of patients. Interestingly, large portions of these variants were described as somatic mosaicism and often escape standard molecular diagnostics using lymphocyte DNA.Here we discuss the role of somatic mosaicism in CdLS and describe two additional patients with NIPBL mosaicism detected by targeted gene panel or exome sequencing. In order to verify the next generation sequencing data, Sanger sequencing or pyrosequencing on DNA extracted from different tissues were applied. None of the pathogenic variants was originally detected by Sanger sequencing on blood DNA.Patient 1 displays an unusual combination of clinical features: he is cognitively only mildly affected, but shows severe limb reduction defects. Patient 2 presents with a moderate phenotype. Interestingly, Sanger sequencing analysis on fibroblast DNA of this patient did not detect the disease-causing variant previously observed on the same DNA sample by exome sequencing. Subsequent analyses could confirm the variants by Sanger sequencing on buccal mucosa DNA. Notably, this is the first report of a higher mutational load in buccal mucosa than in fibroblast cells of a CdLS patient.Detection of low-level mosaicism is of utmost importance for an accurate molecular diagnosis and a proper genetic counseling of patients with a clinical diagnosis of CdLS. Next-generation sequencing technologies greatly facilitate the detection of low-level mosaicism, which might otherwise remain undetected by conventional sequencing approaches. AU - Pozojevic, J.* AU - Parenti, I.* AU - Graul-Neumann, L.* AU - Ruiz Gil, S.* AU - Watrin, E.* AU - Wendt, K.S.* AU - Werner, R.* AU - Strom, T.M. AU - Gillessen-Kaesbach, G.* AU - Kaiser, F.J.* C1 - 52370 C2 - 43939 CY - Po Box 211, 1000 Ae Amsterdam, Netherlands SP - 680-684 TI - Novel mosaic variants in two patients with Cornelia de Lange syndrome. JO - Eur. J. Med. Genet. VL - 61 IS - 11 PB - Elsevier Science Bv PY - 2017 SN - 1769-7212 ER - TY - JOUR AB - Spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2) and familial hemiplegic migraine type 1 (FHM1) are allelic disorders of the gene CACNA1A encoding the P/Q subunit of a voltage gated calcium channel. While SCA6 is related to repeat expansions affecting the C-terminal part of the protein, EA2 and FHM phenotypes are usually associated with nonsense and missense mutations leading to impaired channel properties. In three unrelated families with dominant cerebellar ataxia, symptoms cosegregated with CACNA1A missense mutations of evolutionary highly conserved amino acids (exchanges p.E668K, p.R583Q and p.D302N). To evaluate pathogenic effects, in silico, protein modeling analyses were performed which indicate structural alterations of the novel mutation p.E668K within the homologous domain 2 affecting CACNA1A protein function.The phenotype is characterised by a very slowly progressive ataxia, while ataxic episodes or migraine are uncommon. These findings enlarge the phenotypic spectrum of CACNA1A mutations. AU - Bürk, K.* AU - Kaiser, F.J.* AU - Tennstedt, S.* AU - Schöls, L.* AU - Kreuz, F.R.* AU - Wieland, T. AU - Strom, T.M. AU - Büttner, T.* AU - Hollstein, R.* AU - Braunholz, D.* AU - Plaschke, J.* AU - Gillessen-Kaesbach, G.* AU - Zühlke, C.* C1 - 29314 C2 - 33750 CY - Amsterdam SP - 207-211 TI - A novel missense mutation in CACNA1A evaluated by in silico protein modeling is associated with non-episodic spinocerebellar ataxia with slow progression. JO - Eur. J. Med. Genet. VL - 57 IS - 5 PB - Elsevier Science Bv PY - 2014 SN - 1769-7212 ER - TY - JOUR AB - Mutations in the serine palmitoyltransferase subunit 1 (SPTLC1) gene are the most common cause of hereditary sensory neuropathy type 1 (HSN1). Here we report the clinical and molecular consequences of a particular mutation (p.S331Y) in SPTLC1 affecting a patient with severe, diffuse muscle wasting and hypotonia, prominent distal sensory disturbances, joint hypermobility, bilateral cataracts and considerable growth retardation. Normal plasma sphingolipids were unchanged but 1-deoxy-sphingolipids were significantly elevated. In contrast to other HSN patients reported so far, our findings strongly indicate that mutations at amino acid position Ser331 of the SPTLC1 gene lead to a distinct syndrome. AU - Auer-Grumbach, M.* AU - Bode, H.* AU - Pieber, T.R.* AU - Schabhüttl, M.* AU - Fischer, D.* AU - Seidl, R.* AU - Graf, E. AU - Wieland, T. AU - Schuh, R.* AU - Vacariu, G.* AU - Grill, F.* AU - Timmerman, V.* AU - Strom, T.M. AU - Hornemann, T.* C1 - 26076 C2 - 32057 SP - 266-269 TI - Mutations at Ser331 in the HSN type I gene SPTLC1 are associated with a distinct syndromic phenotype. JO - Eur. J. Med. Genet. VL - 56 IS - 5 PB - Elsevier Science PY - 2013 SN - 1769-7212 ER - TY - JOUR AB - In a male patient with developmental delay, autistic behaviour, obesity, lymphedema, hypertension, macrocephaly, and facial features of chromosome 5p duplication (trisomy 5p) a 3.7 Mb de novo tandem microduplication of 5p13.1-13.2 (rs4703415-rs261752, i.e., chr5:35.62-39.36 Mb) was identified. This observation contributes to the characterization and dissection of the 5p13 duplication syndrome. The possible role of increased NIPBL gene dosage is discussed. AU - Oexle, K.* AU - Hempel, M.* AU - Jauch, A.* AU - Meitinger, T. AU - Rivera-Brugues, N. AU - Stengel-Rutkowski, S.* AU - Strom, T.M. C1 - 4063 C2 - 28573 SP - 225-230 TI - 3.7 Mb tandem microduplication in chromosome 5p13.1-p13.2 associated with developmental delay, macrocephaly, obesity, and lymphedema. Further characterization of the dup(5p13) syndrome. JO - Eur. J. Med. Genet. VL - 54 IS - 3 PB - Elsevier PY - 2011 SN - 1769-7212 ER -