Homozygous and Compound Heterozygous Mutations in the CLCN1 Gene Causes Myotonia in Two Related Saudi Families
Serena Pagliarani1, Alwaleed Alabdulwahed2, Edoardo Monfrini1, Sabrina Lucchiari3, Giacomo Comi1, Alessio Di Fonzo1, Aawadh AlAhmari2, Ahmed Abulaban2, Wafaa AlEyaid4
1Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico,Neurology Unit, Milan, Italy, 2Department of Neurology, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia, 3University of Milan, Department of Pathophysiology and Transplantation (DEPT), Neuroscience Section, Dino Ferrari Centre, Milan, Italy, 4Genetics and Precision Medicine Department, King Abdullah Specialized Children Hospital (KASCH), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA), Riyadh, Saudi Arabia
Objective:
The aim of this project was to find the genetic cause of a classic myotonic phenotype in a consanguineous family in which traditional Sanger sequencing and novel next-generation sequencing (NGS) found no pathogenic variants.
Background:
Non-dystrophic myotonias are rare genetic disorders caused by dysfunction of the CLCN1 or SCN4A genes and are characterized by myotonia, which is the delayed relaxation after a voluntary contraction. CLCN1 causes both dominant and recessive myotonia congenita while SCN4A causes dominant sodium channel myotonia and paramyotonia congenita.
Design/Methods:
The inheritance of the disease in the family was consistent with an autosomal recessive pattern, and our working hypothesis involved a problem in a non-coding region of CLCN1. MLPA analysis and analysis of intronic regions of CLCN1 were conducted.
Results:
MLPA was negative. A pseudogene insertion in intron 14 of CLCN1 was found in homozygosity in the proband and segregated with the disease in his affected siblings. Two affected subjects belonging to another branch of the family presented the insertion of the pseudogene in heterozygosity. Due to the presence of myotonia in both subjects, direct sequencing of CLCN1 was performed and the pathogenic variant c.2789del (p.Pro930Leu*fs18) was found in exon 23 in heterozygosity.
Conclusions:
We found a novel intronic pathogenic variant in CLCN1 that causes myotonia congenita and that had not previously been detected by traditional Sanger sequencing or NGS. Collaboration between neurologists and geneticists is important to resolve cases like this in which the classic diagnostic workup has not led to a diagnosis.
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