A Family Case of Congenital Myasthenic Syndrome-22 Induced by Different Combinations of Molecular Causes in Siblings.
| Title: | A Family Case of Congenital Myasthenic Syndrome-22 Induced by Different Combinations of Molecular Causes in Siblings. |
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| Authors: | Shchagina O; Research Centre for Medical Genetics 1 Moskvorechie St., 115522 Moscow, Russia.; Bessonova L; Research Centre for Medical Genetics 1 Moskvorechie St., 115522 Moscow, Russia.; Bychkov I; Research Centre for Medical Genetics 1 Moskvorechie St., 115522 Moscow, Russia.; Beskorovainaya T; Research Centre for Medical Genetics 1 Moskvorechie St., 115522 Moscow, Russia.; Poliakov A; Research Centre for Medical Genetics 1 Moskvorechie St., 115522 Moscow, Russia. |
| Source: | Genes [Genes (Basel)] 2020 Jul 19; Vol. 11 (7). Date of Electronic Publication: 2020 Jul 19. |
| Publication Type: | Case Reports; Journal Article |
| Language: | English |
| Journal Info: | Publisher: MDPI Country of Publication: Switzerland NLM ID: 101551097 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4425 (Electronic) Linking ISSN: 20734425 NLM ISO Abbreviation: Genes (Basel) Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Basel : MDPI |
| MeSH Terms: | Genotype*; Myasthenic Syndromes, Congenital/*genetics ; Prolyl Oligopeptidases/*genetics; Myasthenic Syndromes, Congenital/pathology ; Child ; Codon, Nonsense ; Humans ; Male ; Pedigree ; RNA Splicing ; Siblings ; Uniparental Disomy |
| Abstract: | Congenital myasthenic syndrome-22 (CMS22, OMIM 616224) is a very rare recessive hereditary disorder. At the moment, ten CMS22 patients are described, with the disorder caused by nine different Loss-of-Function mutations and 14 gross deletions in the PREPL gene. The materials for our study were DNA samples of five family members: two patients with myasthenia, their healthy sibling and parents. Clinical exome analysis was carried out for one patient, then the whole family was checked for target variants with Sanger sequencing, quantitative multiplex ligation-dependent probe amplification, and chromosome 2 microsatellite markers study. To determine the functional significance of the splicing variant, we applied the minigene assay. The cause of the proband's disorder is a compound heterozygous state of two previously non-described pathogenic PREPL variants: a c.1528C>T (p.(Arg510Ter)) nonsense mutation and a c.2094G>T pseudo-missense variant, which, simultaneously with a p.(Lys698Asn) amino acid substitution, affects splicing, leading to exon 14 skipping in mRNA. The second patient's disorder was caused by a homozygous nonsense c.1528C>T (p.(Arg510Ter)) mutation due to maternal uniparental disomy (UPD) of chromosome 2. In this study, we describe a unique case, in which two siblings with a rare disorder have different pathologic genotypes. |
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| Contributed Indexing: | Keywords: CMS22; PREPL; splice site; spliceogenic; uniparental disomy |
| Substance Nomenclature: | 0 (Codon, Nonsense); EC 3.4.21.26 (PREPL protein, human); EC 3.4.21.26 (Prolyl Oligopeptidases) |
| Entry Date(s): | Date Created: 20200726 Date Completed: 20210317 Latest Revision: 20210317 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC7397044 |
| DOI: | 10.3390/genes11070821 |
| PMID: | 32707643 |
| Database: | MEDLINE |
Case Reports; Journal Article