ABSTRACT
We have previously described a heart-, eye-, and brain-malformation syndrome caused by homozygous loss-of-function variants in SMG9, which encodes a critical component of the nonsense-mediated decay (NMD) machinery. Here, we describe four consanguineous families with four different likely deleterious homozygous variants in SMG8, encoding a binding partner of SMG9. The observed phenotype greatly resembles that linked to SMG9 and comprises severe global developmental delay, microcephaly, facial dysmorphism, and variable congenital heart and eye malformations. RNA-seq analysis revealed a general increase in mRNA expression levels with significant overrepresentation of core NMD substrates. We also identified increased phosphorylation of UPF1, a key SMG1-dependent step in NMD, which most likely represents the loss of SMG8--mediated inhibition of SMG1 kinase activity. Our data show that SMG8 and SMG9 deficiency results in overlapping developmental disorders that most likely converge mechanistically on impaired NMD.
Subject(s)
Developmental Disabilities/genetics , Intracellular Signaling Peptides and Proteins/genetics , Nonsense Mediated mRNA Decay , Adolescent , Brain/abnormalities , Child , Child, Preschool , Consanguinity , Developmental Disabilities/metabolism , Family Health , Female , Gene Deletion , Genetic Linkage , Heart Defects, Congenital/genetics , Homozygote , Humans , Infant , Male , Pedigree , Phenotype , Phosphorylation , RNA Helicases/metabolism , RNA, Messenger/metabolism , RNA-Seq , Trans-Activators/metabolism , Young AdultABSTRACT
Ciliopathies are clinical disorders of the primary cilium with widely recognized phenotypic and genetic heterogeneity. In two Arab consanguineous families, we mapped a ciliopathy phenotype that most closely matches Joubert syndrome (hypotonia, developmental delay, typical facies, oculomotor apraxia, polydactyly, and subtle posterior fossa abnormalities) to a single locus in which a founder homozygous truncating variant in FAM149B1 was identified by exome sequencing. We subsequently identified a third Arab consanguineous multiplex family in which the phenotype of Joubert syndrome/oral-facial-digital syndrome (OFD VI) was found to co-segregate with the same founder variant in FAM149B1. Independently, autozygosity mapping and exome sequencing in a consanguineous Turkish family with Joubert syndrome highlighted a different homozygous truncating variant in the same gene. FAM149B1 encodes a protein of unknown function. Mutant fibroblasts were found to have normal ciliogenesis potential. However, distinct cilia-related abnormalities were observed in these cells: abnormal accumulation IFT complex at the distal tips of the cilia, which assumed bulbous appearance, increased length of the primary cilium, and dysregulated SHH signaling. We conclude that FAM149B1 is required for normal ciliary biology and that its deficiency results in a range of ciliopathy phenotypes in humans along the spectrum of Joubert syndrome.
Subject(s)
Abnormalities, Multiple/genetics , Cerebellum/abnormalities , Cilia/pathology , Ciliopathies/diagnosis , Ciliopathies/genetics , Cytoskeletal Proteins/genetics , Eye Abnormalities/genetics , Kidney Diseases, Cystic/genetics , Mutation , Retina/abnormalities , Adolescent , Alleles , Child, Preschool , Cilia/genetics , Consanguinity , Exome , Genes, Recessive , Homozygote , Humans , Male , Nervous System Malformations/genetics , Orofaciodigital Syndromes/genetics , Phenotype , Sequence Analysis, DNA , Signal Transduction , TurkeyABSTRACT
Congenital anomalies of the kidney and urinary tract (CAKUT) are a spectrum of abnormalities affecting morphogenesis of the kidneys and other structures of the urinary tract. Bilateral renal agenesis (BRA) is the most severe presentation of CAKUT. Loss of either nephronectin (NPNT) or its receptor ITGA8 leads to failure of metanephric kidney development with resulting renal agenesis in murine models. Very recently, a single family with renal agenesis and a homozygous truncating variant in NPNT was reported. We report two families in whom genome-wide linkage analysis showed an autozygous locus linked to BRA (at least one member has unilateral renal agenesis) at 4q24, with an LOD score of ~3. Exome sequencing detected a nonsense variant in NPNT in both families within the linkage interval. The pathogenicity of this variant was supported by reverse transcription polymerase chain reaction data showing complete nonsense-mediated decay of the NPNT transcript. Our report confirms the candidacy of NPNT in renal agenesis in humans and shows that even complete loss of function can be compatible with the formation of a single kidney.
Subject(s)
Solitary Kidney , Animals , Congenital Abnormalities , Extracellular Matrix Proteins , Humans , Kidney/abnormalities , Kidney Diseases/congenital , Mice , Urogenital Abnormalities , Vesico-Ureteral RefluxABSTRACT
PURPOSE: Pathogenic variants in Lysyl-tRNA synthetase 1 (KARS1) have increasingly been recognized as a cause of early-onset complex neurological phenotypes. To advance the timely diagnosis of KARS1-related disorders, we sought to delineate its phenotype and generate a disease model to understand its function in vivo. METHODS: Through international collaboration, we identified 22 affected individuals from 16 unrelated families harboring biallelic likely pathogenic or pathogenic in KARS1 variants. Sequencing approaches ranged from disease-specific panels to genome sequencing. We generated loss-of-function alleles in zebrafish. RESULTS: We identify ten new and four known biallelic missense variants in KARS1 presenting with a moderate-to-severe developmental delay, progressive neurological and neurosensory abnormalities, and variable white matter involvement. We describe novel KARS1-associated signs such as autism, hyperactive behavior, pontine hypoplasia, and cerebellar atrophy with prevalent vermian involvement. Loss of kars1 leads to upregulation of p53, tissue-specific apoptosis, and downregulation of neurodevelopmental related genes, recapitulating key tissue-specific disease phenotypes of patients. Inhibition of p53 rescued several defects of kars1-/- knockouts. CONCLUSION: Our work delineates the clinical spectrum associated with KARS1 defects and provides a novel animal model for KARS1-related human diseases revealing p53 signaling components as potential therapeutic targets.
Subject(s)
Hearing Loss , Lysine-tRNA Ligase/genetics , Neurodevelopmental Disorders , Alleles , Animals , Disease Models, Animal , Hearing Loss/genetics , Humans , Neurodevelopmental Disorders/genetics , Phenotype , Zebrafish/geneticsABSTRACT
BACKGROUND AND AIMS: The clinical consequences of defective primary cilium (ciliopathies) are characterized by marked phenotypic and genetic heterogeneity. Although fibrocystic liver disease is an established ciliopathy phenotype, severe neonatal cholestasis is rarely recognized as such. APPROACH AND RESULTS: We describe seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one and necessitating liver transplant in two). Positional mapping revealed a single critical locus on chromosome 7. Whole-exome sequencing revealed three different homozygous variants in Tetratricopeptide Repeat Domain 26 (TTC26) that fully segregated with the phenotype. TTC26 (intraflagellar transport [IFT] 56/DYF13) is an atypical component of IFT-B complex, and deficiency of its highly conserved orthologs has been consistently shown to cause defective ciliary function in several model organisms. We show that cilia in TTC26-mutated patient cells display variable length and impaired function, as indicated by dysregulated sonic hedgehog signaling, abnormal staining for IFT-B components, and transcriptomic clustering with cells derived from individuals with closely related ciliopathies. We also demonstrate a strong expression of Ttc26 in the embryonic mouse liver in a pattern consistent with its proposed role in the normal development of the intrahepatic biliary system. CONCLUSIONS: In addition to establishing a TTC26-related ciliopathy phenotype in humans, our results highlight the importance of considering ciliopathies in the differential diagnosis of severe neonatal cholestasis even in the absence of more typical features.
Subject(s)
Cholestasis, Intrahepatic/genetics , Infant, Newborn, Diseases/genetics , Intracellular Signaling Peptides and Proteins/genetics , Tetratricopeptide Repeat/genetics , Animals , Ciliopathies , Diagnosis, Differential , Hedgehog Proteins , Humans , Infant, Newborn , Mice , Microtubule-Associated Proteins/genetics , Mutation , Protein Transport/genetics , Severity of Illness Index , Exome Sequencing/methodsABSTRACT
PURPOSE: Establishing links between Mendelian phenotypes and genes enables the proper interpretation of variants therein. Autozygome, a rich source of homozygous variants, has been successfully utilized for the high throughput identification of novel autosomal recessive disease genes. Here, we highlight the utility of the autozygome for the high throughput confirmation of previously published tentative links to diseases. METHODS: Autozygome and exome analysis of patients with suspected Mendelian phenotypes. All variants were classified according to the American College of Medical Genetics and Genomics guidelines. RESULTS: We highlight 30 published candidate genes (ACTL6B, ADAM22, AGTPBP1, APC, C12orf4, C3orf17 (NEPRO), CENPF, CNPY3, COL27A1, DMBX1, FUT8, GOLGA2, KIAA0556, LENG8, MCIDAS, MTMR9, MYH11, QRSL1, RUBCN, SLC25A42, SLC9A1, TBXT, TFG, THUMPD1, TRAF3IP2, UFC1, UFM1, WDR81, XRCC2, ZAK) in which we identified homozygous likely deleterious variants in patients with compatible phenotypes. We also identified homozygous likely deleterious variants in 18 published candidate genes (ABCA2, ARL6IP1, ATP8A2, CDK9, CNKSR1, DGAT1, DMXL2, GEMIN4, HCN2, HCRT, MYO9A, PARS2, PLOD3, PREPL, SCLT1, STX3, TXNRD2, WIPI2) although the associated phenotypes are sufficiently different from the original reports that they represent phenotypic expansion or potentially distinct allelic disorders. CONCLUSIONS: Our results should facilitate the timely relabeling of these candidate disease genes in relevant databases to improve the yield of clinical genomic sequencing.
Subject(s)
Disease/genetics , Genomics/methods , Sequence Analysis, DNA/methods , Biological Variation, Population/genetics , Child , Child, Preschool , Diagnosis , Diagnostic Techniques and Procedures , Female , Genetic Testing/standards , Genetic Variation , Genotype , Heredity/genetics , High-Throughput Nucleotide Sequencing/methods , Homozygote , Humans , Infant , Infant, Newborn , Male , Mutation , PhenotypeABSTRACT
Neural tube defects (NTDs) are among the most common birth defects in humans and yet their molecular etiology remains poorly understood. NTDs are believed to result from the complex interaction of environmental factors with a multitude of genetic risk factors in a classical multifactorial disease model. Mendelian forms of NTDs in which single variants are sufficient to cause the disease are extremely rare. We report a monozygotic twin with severe NTDs (occipital encephalocele and myelomeningocele) and a shared de novo, likely truncating, variant in SMARCC1. RTPCR analysis suggests the potential null nature of the variant attributed to nonsense-mediated decay. SMARCC1 is extremely constrained in humans and encodes a highly conserved core chromatin remodeler, BAF155. Mice that are heterozygous for a null allele or homozygous for a hypomorphic allele develop severe NTDs in the form of exencephaly. This is the first report of SMARCC1 mutation in humans, and it shows a critical and conserved requirement for intact BAF chromatin remodeling complex in neurulation. Ann Neurol 2018;83:433-436.
Subject(s)
Neural Tube Defects/genetics , Neural Tube Defects/pathology , Transcription Factors/genetics , Twins, Monozygotic/genetics , Female , Humans , Infant , MutationABSTRACT
Variant nomenclature discrepancy was identified in the article.
ABSTRACT
Skeletal dysplasias are highly variable Mendelian phenotypes. Molecular diagnosis of skeletal dysplasias is complicated by their extreme clinical and genetic heterogeneity. We describe a clinically recognizable autosomal-recessive disorder in four affected siblings from a consanguineous Saudi family, comprising progressive spondyloepimetaphyseal dysplasia, short stature, facial dysmorphism, short fourth metatarsals, and intellectual disability. Combined autozygome/exome analysis identified a homozygous frameshift mutation in RSPRY1 with resulting nonsense-mediated decay. Using a gene-centric "matchmaking" system, we were able to identify a Peruvian simplex case subject whose phenotype is strikingly similar to the original Saudi family and whose exome sequencing had revealed a likely pathogenic homozygous missense variant in the same gene. RSPRY1 encodes a hypothetical RING and SPRY domain-containing protein of unknown physiological function. However, we detect strong RSPRY1 protein localization in murine embryonic osteoblasts and periosteal cells during primary endochondral ossification, consistent with a role in bone development. This study highlights the role of gene-centric matchmaking tools to establish causal links to genes, especially for rare or previously undescribed clinical entities.
Subject(s)
Bone Diseases, Developmental/genetics , Genes, Recessive/genetics , Musculoskeletal Abnormalities/genetics , Mutation/genetics , Ossification, Heterotopic/genetics , Osteochondrodysplasias/genetics , Adolescent , Animals , Bone Diseases, Developmental/pathology , Child , Consanguinity , Deoxyribonucleases, Type II Site-Specific , Dwarfism/genetics , Embryo, Mammalian/cytology , Embryo, Mammalian/metabolism , Exome , Female , Homozygote , Humans , Intellectual Disability/genetics , Male , Mice , Musculoskeletal Abnormalities/pathology , Osteoblasts/metabolism , Osteoblasts/pathology , Osteochondrodysplasias/pathology , Pedigree , Periosteum/metabolism , Periosteum/pathology , Phenotype , Sequence Analysis, DNAABSTRACT
PurposeGenome-wide association studies (GWAS) have been instrumental to our understanding of the genetic risk determinants of complex traits. A common challenge in GWAS is the interpretation of signals, which are usually attributed to the genes closest to the polymorphic markers that display the strongest statistical association. Naturally occurring complete loss of function (knockout) of these genes in humans can inform GWAS interpretation by unmasking their deficiency state in a clinical context.MethodsWe exploited the unique population structure of Saudi Arabia to identify novel knockout events in genes previously highlighted in GWAS using combined autozygome/exome analysis.ResultsWe report five families with homozygous truncating mutations in genes that had only been linked to human disease through GWAS. The phenotypes observed in the natural knockouts for these genes (TRAF3IP2, FRMD3, RSRC1, BTBD9, and PXDNL) range from consistent with, to unrelated to, the previously reported GWAS phenotype.ConclusionWe expand the role of human knockouts in the medical annotation of the human genome, and show their potential value in informing the interpretation of GWAS of complex traits.
Subject(s)
Genome, Human , Genome-Wide Association Study , Genomics , Loss of Function Mutation , Alleles , Facies , Genetic Association Studies , Genetic Predisposition to Disease , Genetics, Population , Genome-Wide Association Study/methods , Genome-Wide Association Study/standards , Genomics/methods , Genomics/standards , Genotype , Humans , Phenotype , Saudi ArabiaABSTRACT
PURPOSE: To describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized. METHODS: Detailed phenotyping and next-generation sequencing (panel and exome). RESULTS: Our analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) of which are novel) in 123 genes with established or tentative links to skeletal dysplasia. In addition, we propose 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we note that our cohort spans 36 established phenotypic categories by the International Skeletal Dysplasia Nosology, as well as 18 novel skeletal dysplasia phenotypes that could not be classified under these categories, e.g., the novel C3orf17-related skeletal dysplasia. We also describe novel phenotypic aspects of well-known disease genes, e.g., PGAP3-related Toriello-Carey syndrome-like phenotype. We note a strong founder effect for many genes in our cohort, which allowed us to calculate a minimum disease burden for the autosomal recessive forms of skeletal dysplasia in our population (7.16E-04), which is much higher than the global average. CONCLUSION: By expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, we hope our study will improve the diagnostic rate of patients with these conditions.
Subject(s)
Exome/genetics , Genetic Heterogeneity , Genetic Predisposition to Disease , Musculoskeletal Abnormalities/genetics , Alleles , Blood Proteins/genetics , Carboxylic Ester Hydrolases , Cohort Studies , Exoribonucleases/genetics , Female , Fetal Proteins/genetics , Founder Effect , Genetics, Population , High-Throughput Nucleotide Sequencing , Humans , Intracellular Signaling Peptides and Proteins/genetics , Male , Membrane Proteins/genetics , Musculoskeletal Abnormalities/classification , Musculoskeletal Abnormalities/pathology , Neoplasm Proteins/genetics , Oncogene Proteins/genetics , Phenotype , Receptors, Cell Surface/genetics , Wnt3A Protein/geneticsABSTRACT
Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease-gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms.
Subject(s)
Exome/genetics , Genetic Heterogeneity , Genetic Markers , Intellectual Disability/genetics , Mutation , Female , Genetic Predisposition to Disease , High-Throughput Nucleotide Sequencing , Humans , Male , Pedigree , Protein ConformationABSTRACT
Ehlers-Danlos syndrome (EDS) describes a group of clinical entities in which the connective tissue, primarily that of the skin, joint and vessels, is abnormal, although the resulting clinical manifestations can vary widely between the different historical subtypes. Many cases of hereditary disorders of connective tissue that do not seem to fit these historical subtypes exist. The aim of this study is to describe a large series of patients with inherited connective tissue disorders evaluated by our clinical genetics service and for whom a likely causal variant was identified. In addition to clinical phenotyping, patients underwent various genetic tests including molecular karyotyping, candidate gene analysis, autozygome analysis, and whole-exome and whole-genome sequencing as appropriate. We describe a cohort of 69 individuals representing 40 families, all referred because of suspicion of an inherited connective tissue disorder by their primary physician. Molecular lesions included variants in the previously published disease genes B3GALT6, GORAB, ZNF469, B3GAT3, ALDH18A1, FKBP14, PYCR1, CHST14 and SPARC with interesting variations on the published clinical phenotypes. We also describe the first recessive EDS-like condition to be caused by a recessive COL1A1 variant. In addition, exome capture in a familial case identified a homozygous truncating variant in a novel and compelling candidate gene, AEBP1. Finally, we also describe a distinct novel clinical syndrome of cutis laxa and marked facial features and propose ATP6V1E1 and ATP6V0D2 (two subunits of vacuolar ATPase) as likely candidate genes based on whole-genome and whole-exome sequencing of the two families with this new clinical entity. Our study expands the clinical spectrum of hereditary disorders of connective tissue and adds three novel candidate genes including two that are associated with a highly distinct syndrome.
Subject(s)
Connective Tissue Diseases/genetics , Genetic Heterogeneity , Genetic Markers/genetics , Skin Abnormalities/genetics , Amino Acid Sequence , Cohort Studies , Connective Tissue Diseases/pathology , Exome/genetics , Female , High-Throughput Nucleotide Sequencing , Humans , Male , Molecular Sequence Data , Pedigree , Phenotype , Sequence Homology, Amino AcidABSTRACT
PURPOSE: Dysmorphology syndromes are among the most common referrals to clinical genetics specialists. Inability to match the dysmorphology pattern to a known syndrome can pose a major diagnostic challenge. With an aim to accelerate the establishment of new syndromes and their genetic etiology, we describe our experience with multiplex consanguineous families that appeared to represent novel autosomal recessive dysmorphology syndromes at the time of evaluation. METHODS: Combined autozygome/exome analysis of multiplex consanguineous families with apparently novel dysmorphology syndromes. RESULTS: Consistent with the apparent novelty of the phenotypes, our analysis revealed a strong candidate variant in genes that were novel at the time of the analysis in the majority of cases, and 10 of these genes are published here for the first time as novel candidates (CDK9, NEK9, ZNF668, TTC28, MBL2, CADPS, CACNA1H, HYAL2, CTU2, and C3ORF17). A significant minority of the phenotypes (6/31, 19%), however, were caused by genes known to cause Mendelian phenotypes, thus expanding the phenotypic spectrum of the diseases linked to these genes. The conspicuous inheritance pattern and the highly specific phenotypes appear to have contributed to the high yield (90%) of plausible molecular diagnoses in our study cohort. CONCLUSION: Reporting detailed clinical and genomic analysis of a large series of apparently novel dysmorphology syndromes will likely lead to a trend to accelerate the establishment of novel syndromes and their underlying genes through open exchange of data for the benefit of patients, their families, health-care providers, and the research community.Genet Med 18 7, 686-695.
Subject(s)
Abnormalities, Multiple/diagnosis , Exome/genetics , Genomics , Hypoglycemia/diagnosis , Microcephaly/diagnosis , Abnormalities, Multiple/genetics , Abnormalities, Multiple/physiopathology , Consanguinity , Disorders of Sex Development/diagnosis , Disorders of Sex Development/genetics , Disorders of Sex Development/physiopathology , Female , High-Throughput Nucleotide Sequencing , Humans , Hypoglycemia/genetics , Hypoglycemia/physiopathology , Male , Microcephaly/genetics , Microcephaly/physiopathology , Mutation , Pedigree , Phenotype , Sequence Analysis, DNA/methodsSubject(s)
Developmental Disabilities/genetics , Megalencephaly/genetics , Mutation, Missense , Nerve Tissue Proteins/genetics , Point Mutation , Abnormalities, Multiple/genetics , Amino Acid Sequence , Amino Acid Substitution , Brain/abnormalities , Dwarfism/genetics , Face/abnormalities , Humans , Infant , Intellectual Disability/genetics , Male , Nerve Tissue Proteins/deficiency , Pedigree , Sequence Alignment , Sequence Homology, Amino AcidSubject(s)
Abnormalities, Multiple , Developmental Disabilities , Brain/diagnostic imaging , Child , Genotype , Homozygote , HumansABSTRACT
Stickler syndrome (SS) is a collagenopathy characterized by arthropathy and vitreoretinopathy with high myopia and cleft palate as common features. In a family with an autosomal recessive SS that does not map to genes known to cause autosomal recessive forms of SS, we combined autozygome and exome analysis to identify a novel missense variant in LOXL3 as the likely candidate cause. LOXL3 cross-links collagen II and its morphants phenocopy the craniofacial defects characteristic of collagen XI deficiency. We propose LOXL3 as a novel candidate gene for autosomal recessive SS.
Subject(s)
Amino Acid Oxidoreductases/genetics , Mutation, Missense , Adolescent , Amino Acid Sequence , Arthritis , Base Sequence , Child , Collagen Diseases/genetics , Connective Tissue Diseases , Consanguinity , Family , Female , Genes, Recessive , Hearing Loss, Sensorineural , Humans , Male , Molecular Sequence Data , Pedigree , Retinal DetachmentABSTRACT
BACKGROUND: Osteogenesis imperfecta (OI) is an hereditary bone disease in which increased bone fragility leads to frequent fractures and other complications, usually in an autosomal dominant fashion. An expanding list of genes that encode proteins related to collagen metabolism are now recognised as important causes of autosomal recessive (AR) OI. Our aim was to study the contribution of known genes to AR OI in order to identify novel loci in mutation-negative cases. METHODS: We enrolled multiplex consanguineous families and simplex cases (also consanguineous) in which mutations in COL1A1 and COL1A2 had been excluded. We used autozygome guided mutation analysis of AR OI (AR OI) genes followed by exome sequencing when such analysis failed to identify the causative mutation. RESULTS: Two simplex and 11 multiplex families were enrolled, encompassing 27 cases. In three multiplex families, autozygosity and linkage analysis revealed a novel recessive OI locus on chromosome 9q31.1-31.3, and a novel truncating deletion of exon 4 of TMEM38B was identified within that interval. In addition, gonadal or gonadal/somatic mosaic mutations in COL1A1 or COL1A2 and homozygous mutations in recently described AR OI genes were identified in all remaining families. CONCLUSIONS: TMEM38B is a novel candidate gene for AR OI. Future studies are needed to explore fully the contribution of this gene to AR OI in other populations.
Subject(s)
Genes, Recessive , Ion Channels/genetics , Mutation , Osteogenesis Imperfecta/genetics , Arabia , Base Sequence , Collagen Type I/genetics , Collagen Type I, alpha 1 Chain , Consanguinity , Exons , Female , Gene Order , Homozygote , Humans , Infant , Infant, Newborn , Male , Osteogenesis Imperfecta/diagnosisABSTRACT
INTRODUCTION: Neurodevelopmental disorders (NDD) are a diverse group of disorders that affect the development of the nervous system. Epilepsy is a common phenotypic aspect of NDD. METHODS: We recruited eight consanguineous families from Pakistan which segregated recessively inherited NDD with epilepsy. Magnetic Resonance imaging (MRI) and Electroencephalogram (EEG) were completed. Exome sequencing was carried out for selected participants from each family. The exome data were analyzed for exonic and splice-site variants that had allele frequencies of less than 0.01 in public databases. RESULTS: Clinical investigations determined that developmental delay, intellectual disability and seizures were manifested by most patients in early childhood. EEG findings were abnormal in the participants of four families. MRI revealed demyelination orcerebral atrophic changes in multiple participants. We identified four novel homozygous variants including nonsense andmissense variants in OCLN, ALDH7A1, IQSEC2 and COL3A1, segregating with the phenotypes in the participants of four families. Previously reported homozygous variants of CNTNAP2, TRIT1 and NARS1 were found in individuals from three families. Clinical utility was observed in directing treatment in case of patients with an ALDH7A1 variant which included pyridoxine administration and enabling accurate counseling about the natural history and recurrence risk. CONCLUSION: Our results add to the clinical and molecular delineation of very rare NDD with epilepsy. The high success rate of exome sequencing is likely attributable to the expectation of homozygous variants in patients of consanguineous families, and in one case, the availability of positional mapping data that greatly aided the variant prioritization.
Subject(s)
Epilepsy , Intellectual Disability , Neurodevelopmental Disorders , Child, Preschool , Humans , Consanguinity , Epilepsy/genetics , Neurodevelopmental Disorders/genetics , Intellectual Disability/genetics , Genomics , Pedigree , Guanine Nucleotide Exchange Factors/geneticsABSTRACT
Despite large sequencing and data sharing efforts, previously characterized pathogenic variants only account for a fraction of Mendelian disease patients, which highlights the need for accurate identification and interpretation of novel variants. In a large Mendelian cohort of 4577 molecularly characterized families, numerous scenarios in which variant identification and interpretation can be challenging are encountered. We describe categories of challenges that cover the phenotype (e.g. novel allelic disorders), pedigree structure (e.g. imprinting disorders masquerading as autosomal recessive phenotypes), positional mapping (e.g. double recombination events abrogating candidate autozygous intervals), gene (e.g. novel gene-disease assertion) and variant (e.g. complex compound inheritance). Overall, we estimate a probability of 34.3% for encountering at least one of these challenges. Importantly, our data show that by only addressing non-sequencing-based challenges, around 71% increase in the diagnostic yield can be expected. Indeed, by applying these lessons to a cohort of 314 cases with negative clinical exome or genome reports, we could identify the likely causal variant in 54.5%. Our work highlights the need to have a thorough approach to undiagnosed diseases by considering a wide range of challenges rather than a narrow focus on sequencing technologies. It is hoped that by sharing this experience, the yield of undiagnosed disease programs globally can be improved.