Digenic Variants in the TTN and TRAPPC11 Genes Co-segregating With a Limb-Girdle Muscular Dystrophy in a Han Chinese Family

Chen, Qian; Zheng, Wen; Xu, Hongbo; Yang, Yan; Song, Zhi; Yuan, Lamei; Deng, Hao

doi:10.3389/fnins.2021.601757

Cited by 6 publications

(3 citation statements)

References 39 publications

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“…These two patients were classified in the undiagnosed group because the molecular diagnosis was not certainly defined with an experimental study. Although digenic inheritance in muscular dystrophies has been described several times between TTN and TRAPPC11 (Chen et al, 2021), DES and CAPN3 (Peddareddygari et al, 2018), and LMNA and EMD (Yaou et al, 2007) genes, there are no functional studies on the evidence of digenic inheritance. Because two of our patients were the only affected individuals in their family, segregation analysis of the variants could not be clear evidence to prove the digenic inheritance, even if the variants of U26 were detected in the trans position.…”

Section: Patientmentioning

confidence: 99%

High diagnostic yield of targeted next‐generation sequencing panel as a first‐tier molecular test for the patients with myopathy or muscular dystrophy

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Köken

Satılmış

et al. 2022

Annals of Human Genetics

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Muscular dystrophies are a heterogeneous group of neuromuscular disorders with a wide range of the clinical and genetic spectrum. Whole-exome sequencing (WES) has been on the rise to become the usual method of choice for molecular diagnosis in patients presenting with muscular dystrophy or congenital or metabolic myopathy phenotype. Here, we used a panel with 47 genes including not only muscular dystrophy but also myopathy-associated genes that had been used as a first-tier approach. A total of 146 patients who were referred to our clinic with the prediagnosis of muscular dystrophy and/or myopathy were included in the study. Dystrophin gene deletion/duplication was ruled out on the patients with a preliminary diagnosis of Duchenne muscular dystrophy. In this study, the molecular etiology of 67 patients was proved with the gene panel with a diagnostic yield of 46%. Causal variants were identified in 23 genes including CAPN3(11), DYSF(9), DMD(8), SGCA(5), TTN(4), LAMA2(3), LMNA(3), SGCB(3), COL6A1(3), DES (2), CAV3(2), FKRP(2), FKTN(2), ANO5, COL6A2, CLCN1, GNE, POMGNT1, POMGNT2, POMT2, SYNE1, TCAP, and FLNC with 16 novel variants. There were 27 patients with uncertain molecular results including the ones who had a variant of uncertain significance, who had only one heterozygous variant for an autosomal recessive disease, and the ones who had two variants in different genes. Molecular diagnosis in muscular dystrophy is essential to plan clinical management and choosing treatment options. Also, the results will affect the reproduction options. Targeted next-generation sequencing is a cost-effective method that reduces the WES requirements with a significant diagnostic rate.

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Section: Patientmentioning

confidence: 99%

High diagnostic yield of targeted next‐generation sequencing panel as a first‐tier molecular test for the patients with myopathy or muscular dystrophy

Çavdarlı

Köken

Satılmış

et al. 2022

Annals of Human Genetics

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“…While digenic inheritance has been widely recognized in association with, for example, deafness 26 , 27 and cardiovascular conditions 28 , only a handful of digenic cases have been reported in the neuromuscular field. These are, however, mostly single cases 29 , 30 , with only SQSTM1 / TIA1 multisystem proteinopathy (MPS) 31 and D4Z4/SMCHD1 facioscapulohumeral muscular dystrophy type 2 (FSHD2; ref. 32 ) being replicated in independent cohorts.…”

Section: Discussionmentioning

confidence: 99%

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy

Töpf,

Cox,

Zaharieva

et al. 2024

Nat Genet

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In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3−/−; ttn.1+/−) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases.

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“…To collect data for training purposes, we curated a dataset of pathogenic digenic combinations extracted both from DIDA 26 , from literature review [29][30][31][32] and from an internal unpublished database. Variants have been reported with their genomic coordinates and associated with the caused phenotypes expressed as Human Phenotype Ontology (HPO) terms 33 , if explicitly available.…”

Section: Dataset Description 211 Training Data Collection and Preproc...mentioning

confidence: 99%

Digenic variant interpretation with hypothesis-driven explainable AI

Paoli,

Nicora,

Berardelli

et al. 2023

Preprint

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MotivationThe digenic inheritance hypothesis holds the potential to enhance diagnostic yield in rare diseases. Computational approaches capable of accurately interpreting and prioritizing digenic combinations based on the proband’s phenotypic profiles and familial information can provide valuable assistance to clinicians during the diagnostic process.ResultsWe have developed diVas, a hypothesis-driven machine learning approach that can effectively interpret genomic variants across different gene pairs. DiVas demonstrates strong performance both in classifying and prioritizing causative pairs, consistently placing them within the top positions across 11 real cases (achieving 73% sensitivity and a median ranking of 3). Additionally, diVas exploits Explainable Artificial Intelligence (XAI) to dissect the digenic disease mechanism for predicted positive pairs.Availability and ImplementationPrediction results of the diVas method on a high-confidence, comprehensive, manually curated dataset of known digenic combinations are available atoliver.engenome.com.

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Digenic Variants in the TTN and TRAPPC11 Genes Co-segregating With a Limb-Girdle Muscular Dystrophy in a Han Chinese Family

Cited by 6 publications

References 39 publications

High diagnostic yield of targeted next‐generation sequencing panel as a first‐tier molecular test for the patients with myopathy or muscular dystrophy

High diagnostic yield of targeted next‐generation sequencing panel as a first‐tier molecular test for the patients with myopathy or muscular dystrophy

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy

Digenic variant interpretation with hypothesis-driven explainable AI

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