Open AccessCongenital Hypotonia: Cracking a SAGA of consanguineous kindred harboring four genetic variants
Author(s) -
Kalfon Limor,
Baydany Meirav,
Samra Nadra,
Heno Nawaf,
Segal Zvi,
Eran Ayelet,
Yulevich Alon,
Fellig Yakov,
Mandel Hanna,
FalikZaccai Tzipora C.
Publication year - 2022
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.1849
Subject(s) - hypotonia , exome sequencing , disease gene identification , genetics , genetic counseling , population , consanguinity , genetic heterogeneity , medicine , genetic linkage , exome , genetic testing , biology , mutation , gene , phenotype , environmental health
Abstract Background We aimed to determine the molecular and biochemical basis of an extended highly consanguineous family with multiple children presenting severe congenital hypotonia. Methods Clinical investigations, homozygosity mapping, linkage analyses and whole exome sequencing, were performed. mRNA and protein levels were determined. Population screening was followed. Results We have identified a novel nonsense variant in NGLY1 in two affected siblings, and compound heterozygosity for three novel RYR1 variants in two affected sisters from another nuclear family within the broad pedigree. Population screening revealed a high prevalence of carriers for both diseases. The genetic variants were proven to be pathogenic, as demonstrated by western blot analyses. Conclusions Revealing the genetic diagnosis enabled us to provide credible genetic counselling and pre‐natal diagnosis to the extended family and genetic screening for this high‐risk population. Whole exome/genome sequencing should be the first tier tool for accurate determination of the genetic basis of congenital hypotonia. Two different genetic disorders within a large consanguineous pedigree should be always considered.