Identification of Compound Heterozygous Variants: a Case Report

Overview

Journal Transl Pediatr

Publisher AME Publishing Company

Specialty Pediatrics

Date 2024 Jul 10

PMID 38984033

Authors

Yingchao Ying

Jia Ye

Jue Shen

Guojuan Chen

Kewen Jiang

Affiliations

Soon will be listed here.

Abstract

Background: Laminin-α2 () chain-deficient muscular dystrophy (-MD) is the most common congenital muscular dystrophy (CMD) in the world. Its main manifestations are muscle weakness and hypotonia that occur after birth or at early infancy.

Case Description: We reported a case of a 3-year-old and 6-month-old boy presented with delayed motor development, elevated creatine kinase (CK) levels, and abnormal white matter in the brain. Whole exome sequencing (WES) showed compound heterozygous variants of the gene. This case reports for the first time the compound heterozygous variants c.5476C>T (p.R1826*) (paternal inheritance) with c.2749 + 2dup (maternal inheritance), as both variants are interpreted as pathogenic/potentially pathogenic variants.

Conclusions: This study reports a novel heterozygous variant, including two pathogenic variants in the gene, and highlights the effectiveness of highly efficient exome sequencing applying in patients with undefined CMDs.

References

Yamamoto-Shimojima K, Ono H, Imaizumi T, Yamamoto T . Novel variants identified in a patient with white matter abnormalities. Hum Genome Var. 2020; 7:16. PMC: 7248065. DOI: 10.1038/s41439-020-0103-5. View

Naom I, dAlessandro M, Sewry C, PHILPOT J, Manzur A, Dubowitz V . Laminin alpha 2-chain gene mutations in two siblings presenting with limb-girdle muscular dystrophy. Neuromuscul Disord. 1998; 8(7):495-501. DOI: 10.1016/s0960-8966(98)00065-0. View

Jaganathan K, Kyriazopoulou Panagiotopoulou S, McRae J, Fazel Darbandi S, Knowles D, Li Y . Predicting Splicing from Primary Sequence with Deep Learning. Cell. 2019; 176(3):535-548.e24. DOI: 10.1016/j.cell.2018.12.015. View

Urquia-Osorio H, Pimentel-Silva L, Rezende T, Almendares-Bonilla E, Yasuda C, Concha L . Superficial and deep white matter diffusion abnormalities in focal epilepsies. Epilepsia. 2022; 63(9):2312-2324. DOI: 10.1111/epi.17333. View

Saredi S, Gibertini S, Matalonga L, Farina L, Ardissone A, Moroni I . Exome sequencing detects compound heterozygous nonsense LAMA2 mutations in two siblings with atypical phenotype and nearly normal brain MRI. Neuromuscul Disord. 2019; 29(5):376-380. DOI: 10.1016/j.nmd.2019.04.001. View

Lokken N, Born A, Duno M, Vissing J . LAMA2-related myopathy: Frequency among congenital and limb-girdle muscular dystrophies. Muscle Nerve. 2015; 52(4):547-53. DOI: 10.1002/mus.24588. View

Sarkozy A, Foley A, Zambon A, Bonnemann C, Muntoni F . LAMA2-Related Dystrophies: Clinical Phenotypes, Disease Biomarkers, and Clinical Trial Readiness. Front Mol Neurosci. 2020; 13:123. PMC: 7419697. DOI: 10.3389/fnmol.2020.00123. View

Tran V, Nguyen N, Tran L, Thi Le P, Tran A, Pham T . Merosin-deficient congenital muscular dystrophy type 1a: detection of variants in Vietnamese patients. Front Genet. 2023; 14:1183663. PMC: 10301838. DOI: 10.3389/fgene.2023.1183663. View

Mito R, Pedersen M, Pardoe H, Parker D, Smith R, Cameron J . Exploring individual fixel-based white matter abnormalities in epilepsy. Brain Commun. 2024; 6(1):fcad352. PMC: 10768884. DOI: 10.1093/braincomms/fcad352. View

10.

Miyagoe-Suzuki Y, Nakagawa M, Takeda S . Merosin and congenital muscular dystrophy. Microsc Res Tech. 2000; 48(3-4):181-91. DOI: 10.1002/(SICI)1097-0029(20000201/15)48:3/4<181::AID-JEMT6>3.0.CO;2-Q. View

11.

Xiong H, Tan D, Wang S, Song S, Yang H, Gao K . Genotype/phenotype analysis in Chinese laminin-α2 deficient congenital muscular dystrophy patients. Clin Genet. 2014; 87(3):233-43. DOI: 10.1111/cge.12366. View

12.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17(5):405-24. PMC: 4544753. DOI: 10.1038/gim.2015.30. View

13.

Zambon A, Muntoni F . Congenital muscular dystrophies: What is new?. Neuromuscul Disord. 2021; 31(10):931-942. DOI: 10.1016/j.nmd.2021.07.009. View

14.

Wang D, Li B, Ma Q, Yu Z, Chen K, He Y . Novel compound heterozygous mutations of LAMA2-limb-girdle muscular dystrophy: A case report and literature review. Front Neurol. 2023; 14:1078151. PMC: 9968920. DOI: 10.3389/fneur.2023.1078151. View

15.

Cauley E, Pittman A, Mummidivarpu S, Karimiani E, Martinez S, Moroni I . Novel mutation identification and copy number variant detection via exome sequencing in congenital muscular dystrophy. Mol Genet Genomic Med. 2020; 8(11):e1387. PMC: 7667317. DOI: 10.1002/mgg3.1387. View

16.

Previtali S, Zambon A . LAMA2 Neuropathies: Human Findings and Pathomechanisms From Mouse Models. Front Mol Neurosci. 2020; 13:60. PMC: 7190814. DOI: 10.3389/fnmol.2020.00060. View

17.

Ge L, Zhang C, Wang Z, Chan S, Zhu W, Han C . Congenital muscular dystrophies in China. Clin Genet. 2019; 96(3):207-215. DOI: 10.1111/cge.13560. View

18.

El Kadiri Y, Ratbi I, Laarabi F, Kriouile Y, Sefiani A, Lyahyai J . Identification of a novel LAMA2 c.2217G > A, p.(Trp739*) mutation in a Moroccan patient with congenital muscular dystrophy: a case report. BMC Med Genomics. 2021; 14(1):113. PMC: 8060993. DOI: 10.1186/s12920-021-00959-2. View