2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Impact of processed pseudogene insertions in genetic testing as cause of monogenic diseases: insertion in <em>CLCN1 </em>gene causing Myotonia Congenita

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This study discusses the impact of processed pseudogene insertions in genetic testing as a cause of monogenic diseases, specifically focusing on a case of autosomal recessive myotonia congenita. Myotonia congenita is a rare muscle disorder characterized by muscle stiffness and the inability of muscles to relax after contraction. It is caused by mutations in the CLCN1 gene.<br /><br />The study reports on a 3-year-old female patient who presented with myotonia at 14 months of age. Genomic sequencing was performed to identify the causative variant, but no good candidate was initially found. Structural variants were then considered, and a deep intronic homozygous insertion of approximately 750bp was identified in intron 14 of the CLCN1 gene.<br /><br />Further investigation showed that the inserted region mapped exclusively to the coding region and UTR of the UQCRH gene, which is unrelated to myotonia congenita. It was suspected that this insertion was the result of a retrotransposition event. However, because CLCN1 is not expressed in the available sample (peripheral blood), RNA-sequencing was not feasible. CLCN1 is primarily expressed in skeletal muscle and testis.<br /><br />The study concludes that this case is the third reported instance of a processed pseudogene insertion causing a monogenic disorder. The analysis of structural variants in genomic sequencing is challenging and time-consuming but can effectively screen for processed pseudogene insertions. The study highlights the importance of genomic sequencing as a first-tier approach for the diagnosis of rare disorders.<br /><br />Overall, this study provides valuable insights into the impact of processed pseudogene insertions in genetic testing and emphasizes the role of genomic sequencing in diagnosing rare disorders.

Asset Subtitle

Co-Author - Kornelia Tripolszki, PhD; Co-Author - Javier Martini, MD; Co-Author - Kapil Kampe, PhD; Co-Author - Vasiliki Karageorgou, MSc; Co-Author - Mohamed Almuhaizea, MD; Co-Author - Catarina Pereira, MSc; Co-Author - Stephanie Weissgraeber, PhD; Co-Author - Omid Paknia, PhD; Presenting Author - Jorge Pinto-Basto, MD; Co-Author - Peter B. Bauer, MD;

Meta Tag

Genetic Testing

Genome sequencing

Genomic Methodologies

Musculoskeletal system

NextGen Sequencing

Sequencing

Variant Detection

Co-Author Kornelia Tripolszki, PhD

Co-Author Javier Martini, MD

Co-Author Kapil Kampe, PhD

Co-Author Vasiliki Karageorgou, MSc

Co-Author Mohamed Almuhaizea, MD

Co-Author Catarina Pereira, MSc

Co-Author Stephanie Weissgraeber, PhD

Co-Author Omid Paknia, PhD

Co-Author Peter B. Bauer, MD

Presenting Author Jorge Pinto-Basto, MD

Keywords

processed pseudogene insertions

genetic testing

monogenic diseases

autosomal recessive myotonia congenita

CLCN1 gene

muscle disorder

genomic sequencing

structural variants

retrotransposition event

rare disorders