The congenital muscular dystrophies (CMD) are a heterogeneous group of autosomal recessive disorders. A new pathomechanism has recently been identified in a group of these disorders in which known or putative glycosyltransferases are defective. Common to all these conditions is the hypoglycosylation of alpha-dystroglycan. Fukuyama CMD, muscle-eye-brain disease and Walker-Warburg syndrome, each associated with eye abnormalities and neuronal migration defects, result from mutations in fukutin, POMGnT1 and POMT1, respectively, while mutations in the fukutin-related protein (FKRP) gene cause congenital muscular dystrophy 1C, typically lacking brain involvement. Another putative glycosyltransferase, Large, is mutated in the myodystrophy mouse. The human homologue of this gene is therefore a strong candidate for involvement in novel forms of muscular dystrophy. We studied 36 patients with muscular dystrophy and either mental retardation, structural brain changes or abnormal alpha-dystroglycan immunolabelling, unlinked to any reported CMD loci. Linkage analysis in seven informative families excluded involvement of LARGE but sequencing of this gene in the remaining 29 families identified one patient with a G1525A (Glu509Lys) missense mutation and a 1 bp insertion, 1999insT. This 17-year-old girl presented with congenital muscular dystrophy, profound mental retardation, white matter changes and subtle structural abnormalities on brain MRI. Her skeletal muscle biopsy showed reduced immunolabelling of alpha-dystroglycan. Immunoblotting with an antibody to a glycosylated epitope demonstrated a reduced molecular weight form of alpha-dystroglycan that retained some laminin binding activity. This is the first description of mutations in the human LARGE gene and we propose to name this new disorder MDC1D.

Spinal muscular atrophies (SMA, also known as hereditary motor neuropathies) and hereditary motor and sensory neuropathies (HMSN) are clinically and genetically heterogeneous disorders of the peripheral nervous system. Here we report that mutations in the TRPV4 gene cause congenital © 2009 Nature America, Inc. All rights reserved.Correspondence should be addressed to M.A.-G. (michaela.auergrumbach@medunigraz.at).. METHODS: Methods and any associated references are available in the online version of the paper at http://www.nature.com/ naturegenetics/. Accession codes. GenBank: human TRPV4 cDNA, NM_021625; human TRPV4, NP_067638 IsoA. Pfam: ankyrin repeat, PF00023.Note: Supplementary information is available on the Nature Genetics website. AUTHOR CONTRIBUTIONS: M.A.-G., S.U., J.S., M.E.M., A.H.C., K.J.D., C.M.A.v.R.-A., N.E.A., H.L., B.S.-W., R.P., C.L., G.W.P., H.J.S., H.K. and T.R.P. recruited the study participants, acquired clinical data, conducted neurological and neurophysiological evaluations and performed linkage analysis. M.A.-G, C.G., L.P. and C.F. carried out the Affymetrix array linkage studies and identified the mutations. A.O., Z.B. and B.T. designed, carried out and analyzed the electrophysiological and Ca 2+ -imaging studies. E.F. conducted immunofluorescence and immunohistochemistry studies. H.S. conducted fluorescence-activated cell sorting (FACS) and biotinylation studies. A.K. performed structural biology and biocomputing analyses. A.H.C., M.E.M. and H.K. participated in the data analysis and reviewed the manuscript. M.A.-G. and C.G. analyzed the data, designed and supervised the study and wrote the manuscript. Supplementary Fig. 1) and observed linkage to three chromosomal regions with log 10 of odds (lod) scores >2 for several SNP markers, including the chromosome 12q23-24 region (data not shown). We constructed haplotypes by including additional distantly related family members (right branch of the pedigree; Supplementary Fig. 1). The genetic interval transmitted with the disease resides between SNPs rs2374688 and rs35426 (Chr. 12: 106,197,054,429 bp; Supplementary Table 1) and overlaps with the intervals reported for risk of congenital distal SMA, SPSMA and HMSN2C 2-4 . Europe PMC Funders GroupIn an affected individual from family FAM_1, we began sequencing all protein-coding exons and exon-intron boundaries of 19 genes but initially observed only known SNPs (Supplementary Table 2). However, sequencing of all protein-coding exons of TRPV4 (transient receptor potential vanilloid 4; chr. 12: 108,705,277-108,755,595; reverse strand) revealed a heterozygous C-to-T nucleotide change at position 943 in exon 6 (Supplementary Fig. 2a), which is predicted to cause the substitution of arginine with tryptophan at position 315 of TRPV4 (R315W). We then screened DNA samples from additional families showing one of the phenotypes described above, including two families previously reported 1,3,4 . All affected individuals from the chromosome 12q23-24-linked family (here called FAM_2) described by...

Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.

Our results expand the spectrum of brain involvement associated with mutations in LARGE, POMGnT1, POMT1, and POMT2. Pontine clefts were visible in some dystroglycanopathy patients. Infratentorial structures were often affected in isolation, highlighting their susceptibility to involvement in these conditions.

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Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal-dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca2+ sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin–actin association or tropomyosin head-to-tail binding.

Ryanodine receptor 1 (RYR1) mutations are a common cause of congenital myopathies associated with both dominant and recessive inheritance. Histopathological findings frequently feature central cores or multi-minicores, more rarely, type 1 predominance/uniformity, fiber-type disproportion, increased internal nucleation, and fatty and connective tissue. We describe 71 families, 35 associated with dominant RYR1 mutations and 36 with recessive inheritance. Five of the dominant mutations and 35 of the 55 recessive mutations have not been previously reported. Dominant mutations, typically missense, were frequently located in recognized mutational hotspot regions, while recessive mutations were distributed throughout the entire coding sequence. Recessive mutations included nonsense and splice mutations expected to result in reduced RyR1 protein. There was wide clinical variability. As a group, dominant mutations were associated with milder phenotypes; patients with recessive inheritance had earlier onset, more weakness, and functional limitations. Extraocular and bulbar muscle involvement was almost exclusively observed in the recessive group. In conclusion, our study reports a large number of novel RYR1 mutations and indicates that recessive variants are at least as frequent as the dominant ones. Assigning pathogenicity to novel mutations is often difficult, and interpretation of genetic results in the context of clinical, histological, and muscle magnetic resonance imaging findings is essential.

Progressive external ophthalmoplegia (PEO) is a canonical feature of mitochondrial disease, but in many patients its genetic basis is unknown. Using exome sequencing, Pfeffer et al. identify mutations in SPG7 as an important cause of PEO associated with spasticity and ataxia, and uncover evidence of disordered mtDNA maintenance in patients.