Congenital Hypotonia: Cracking a SAGA of consanguineous kindred harboring four genetic variants. Issue 1 (31st December 2021)

• Record Type: Journal Article
• Authors: Kalfon, Limor; Baydany, Meirav; Samra, Nadra; Heno, Nawaf; Segal, Zvi; Eran, Ayelet; Yulevich, Alon; Fellig, Yakov; Mandel, Hanna; Falik‐Zaccai, Tzipora C.
• Is Part Of: Molecular genetics & genomic medicine. Volume 10:Issue 1(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-12-31
• Subjects: consanguineous kindred -- hypotonia -- whole exome/genome sequencing; Medical genetics -- Periodicals; Genomics -- Periodicals; 616.042
• DOI: 10.1002/mgg3.1849
• Languages: English
• ISSNs: 2324-9269

Abstract

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. Abstract : We report the molecular and biochemical basis of an extended highly consanguineous family with five children presenting severe congenital hypotonia who underwent a 'diagnostic odyssey.' 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. Whole exome/genome sequencing should be first tier tool for accurate genetic diagnosis of congenital hypotonia; two different genetic disorders within a large consanguineous pedigree should be always considered.