Neuromuscular disease genetics in under-represented populations: increasing data diversity

Brain, Journal Year: 2023, Volume and Issue: 146(12), P. 5098 - 5109

Published: July 30, 2023

Abstract Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle countries (LMICs) with limited access diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked inequality hampers understanding of diversity hinders accurate all settings. We developed a cloud-based transcontinental partnership build diverse, deeply-phenotyped genetically characterized cohorts improve architecture knowledge, potentially advance clinical management. connected 18 centres Brazil, India, South Africa, Turkey, Zambia, Netherlands the UK. co-developed solution trained 17 international neurology fellows genomic interpretation. Single gene whole exome were analysed via bespoke bioinformatics pipeline reviewed alongside phenotypic global webinars inform outcome decisions. recruited 6001 participants first 43 months. Initial analyses ‘solved’ or ‘possibly solved’ ∼56% probands overall. In-depth review four commonest categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies Duchenne/Becker dystrophy) delivered ∼59% ∼13% outcome. Almost 29% disease causing variants novel, increasing diverse pathogenic variant knowledge. Unsolved represent new discovery cohort. The dataset provides large resource under-represented populations for translational research. conclusion, we established remote assess NMDs across populations. It supported diagnosis, enabling counselling, eligibility trials. Similar virtual partnerships could be adopted by other areas neurological practice reduce benefit patients

Language: Английский

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Biallelic variants in AGRN with recurrent pregnancy losses in a family with a fetal akinesia deformation sequence

Clinical Dysmorphology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

Agrin, encoded by AGRN, plays a vital role in the acetylcholine receptor clustering pathway, and any defects this pathway are known to cause congenital myasthenic syndrome (CMS) 8 early childhood with variable fatigable muscle weakness. The most severe or lethal form of CMS manifests as fetal akinesia deformation sequence (FADS). To date, only one family has been reported an association null variants AGRN FADS. We identified nonconsanguineous couple recurrent pregnancy loss. Detailed phenotyping fetuses was performed via perinatal autopsy. Genetic evaluation along split-read analysis identify variants. Perinatal revealed FADS family, genomic testing novel AGRN. First, whole-exome sequencing maternally inherited heterozygous variant c.952+1_952+3del fetuses. Split-read exome led identification paternally second variant, deletion 41.33 kb, encompassing exons 1 2 This study highlights importance incorporating clinical practice emphasizes best our knowledge, is report explaining

Language: Английский

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Endogamy and high prevalence of deleterious mutations in India: evidence from strong founder events

Journal of genetics and genomics/Journal of Genetics and Genomics, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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Biallelic Variant, c.644‐13_644‐9del in UNC50 Is Associated With Congenital Myasthenia Syndrome

American Journal of Medical Genetics Part A, Journal Year: 2025, Volume and Issue: unknown

Published: April 12, 2025

UNC50 encodes a transmembrane protein that plays crucial role in L-acetylcholine receptor trafficking and thus cholinergic transmission at the neuromuscular junction. Previously, biallelic loss-of-function variant was reported an individual with lethal arthrogryposis multiplex congenita. We herein describe affected individuals from two unrelated families congenita one family severe early-onset dysfunction other, both within spectrum of congenital myasthenia syndrome. A variant, c.644-13_644-9del, p.? intron 5 (NM_014044.7) identified families. Transcript analysis peripheral blood cDNA heterozygous carrier parents 1 revealed c.644-13_644-9del leads to aberrant splicing. With these findings, we validated association disease-causing variants

Language: Английский

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Further delineation of defects in MRPS2 causing human OXPHOS deficiency and early developmental abnormalities in zebrafish

European Journal of Human Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: May 13, 2025

Abstract Mitochondrial ribosomal protein-small 2 ( MRPS2 ) encodes a vital structural protein essential for assembling mitoribosomal small subunit and thus mitochondrial translation. Any defect in translation impacts OXPHOS activity cellular respiration. Defects have been implicated recently four families with combined oxidative phosphorylation deficiency-36 (MIM# 617950). We herein describe two individuals from unrelated variable phenotypes of acute onset severe metabolic decompensation symptomatic hypoglycemia. Exome sequencing identified bi-allelic variants (NM_016034.5) the affected individuals: P1: c.490 G > A p.(Glu164Lys); P2: c.413 p.(Arg138His). Further evaluation variant p.(Glu164Lys) patient-derived skin fibroblasts revealed decreased expression transcript levels along complex I IV proteins. Proteomics analysis proteins increased large Also, reduced enzyme activities, respiration (OCR), altered morphology on confocal imaging were observed. Additionally, mrps2 knockout zebrafish larvae demonstrated an abnormal developmental phenotype Complex activity. With these findings, we identify additional , illustrating clinical spectrum validate pathogenicity defects through in-vitro in-vivo assays.

Language: Английский

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Perspectives on the future of dysmorphology

American Journal of Medical Genetics Part A, Journal Year: 2022, Volume and Issue: 191(3), P. 659 - 671

Published: Dec. 9, 2022

Abstract The field of clinical genetics and genomics continues to evolve. In the past few decades, milestones like initial sequencing human genome, dramatic changes in technologies, introduction artificial intelligence, have upended offered fascinating new insights. Though difficult predict precise paths will follow, rapid change may continue be inevitable. Within genetics, practice dysmorphology, as defined by pioneering geneticist David W. Smith 1960s “the study of, or general subject abnormal development tissue form” has also been affected technological advances well more trends biomedicine. To address possibilities, potential, perils regarding future a group geneticists, representing different career stages, areas focus, geographic regions, contributed this piece providing insights about how dysmorphology develop over next several decades.

Language: Английский

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Genetic and phenotypic landscape of pediatric‐onset epilepsy in 142 Indian families: Counseling and therapeutic implications

Clinical Genetics, Journal Year: 2024, Volume and Issue: 105(6), P. 639 - 654

Published: Feb. 19, 2024

Abstract The application of genomic technologies has led to unraveling the complex genetic landscape disorders epilepsy, gaining insights into their underlying disease mechanisms, aiding precision medicine, and providing informed counseling. We herein present phenotypic genotypic from 142 Indian families with epilepsy or without comorbidities. Based on electroclinical findings, syndrome diagnosis could be made in 44% (63/142) adopting latest proposal for classification by ILAE task force (2022). Of these, 95% (60/63) exhibited syndromes developmental epileptic encephalopathy progressive neurological deterioration. A definitive molecular was achieved 74 (52%) families. Infantile‐onset noted 81% these (61/74). Fifty‐five monogenic, four chromosomal, one imprinting disorder were identified variants included 65 (96%) single‐nucleotide variants/small insertion‐deletions, 1 (2%) copy‐number variant, triplet‐repeat expansion 53 epilepsy‐associated genes causing monogenic disorders. 35 novel. Therapeutic implications 51% (38/74) diagnosis. Forty‐one out 66 autosomal recessive inherited dominant high risk recurrence.

Language: Английский

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Two sisters with RSPRY1‐related spondyloepimetaphyseal dysplasia

American Journal of Medical Genetics Part A, Journal Year: 2024, Volume and Issue: 194(8)

Published: April 2, 2024

Biallelic variants in RSPRY1 have been found to result spondyloepimetaphyseal dysplasia. Two siblings presenting with short stature, facial dysmorphism, progressive vertebral defects, small epiphysis, cupping and fraying of metaphyses, brachydactyly, metatarsals harbored a homozygous missense variant c.1652G>A;p.(Cys551Tyr) the gene. The phenotype our patients resembles dysplasia, Faden-Alkuraya type. Thus, study provides further evidence support association We observed joint dislocation as novel clinical feature this condition.

Language: Английский

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Biallelic loss of function variants in FUZ result in an orofaciodigital syndrome

European Journal of Human Genetics, Journal Year: 2024, Volume and Issue: 32(8), P. 1022 - 1026

Published: May 3, 2024

Orofaciodigital syndrome is a distinctive subtype of skeletal ciliopathies. Disease-causing variants in the genes encoding CPLANE complex result wide variety dysplasia with disturbed ciliary functions. The phenotypic spectrum includes orofaciodigital and short rib polydactyly syndrome. FUZ, as part complex, involved intraflagellar vesicular trafficking within primary cilia. Previously, variants, c.98_111+9del c.851G>T FUZ were identified two individuals ciliopathy, manifesting digital anomalies (polydactyly, syndactyly), orofacial cleft, ribs cardiac defects. Here, we present novel c.601G>A c.625_636del biallelic state, additional subjects exhibiting overlap previously reported cases. Our findings underscore association between loss function ciliopathy akin to

Language: Английский

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Genome sequencing enables diagnosis and treatment of SLC5A6 neuropathy

European Journal of Human Genetics, Journal Year: 2024, Volume and Issue: 32(8), P. 947 - 953

Published: May 30, 2024

Language: Английский

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