Abstract Details

Title Homozygous and Compound Heterozygous Mutations in the CLCN1 Gene Causes Myotonia in Two Related Saudi Families

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P2 - Poster Session 2 (8:00 AM-9:00 AM)

Poster/Presentation
Number 11-032

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.

Authors/Disclosures
Alwaleed Alabdulwahed, MBBS (MNGHA) PRESENTER	Dr. Alabdulwahed has nothing to disclose.
Serena Pagliarani	Serena Pagliarani has nothing to disclose.
Edoardo Monfrini, MD (University of Milan)	Dr. Monfrini has nothing to disclose.
Sabrina Lucchiari, PhD	Dr. Lucchiari has nothing to disclose.
Giacomo Comi	Giacomo Comi has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta. Giacomo Comi has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis.
Alessio D. Di Fonzo (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico)	No disclosure on file
Awadh Alahmari, MBBS (Ngh)	Dr. Alahmari has nothing to disclose.
Ahmad Abulaban, MD, FAAN (King Abdulaziz Medical City)	Dr. Abulaban has nothing to disclose.
Wafaa Eyaid	Dr. Eyaid has nothing to disclose.

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