ABSTRACT
Limb girdle muscular dystrophies (LGMD) are a genetically heterogeneous group of muscular dystrophies. The study presents an overview of molecular characteristics of a large cohort of LGMD patients who are representative of the Czech LGMD population. We present 226 LGMD probands in which 433 mutant alleles carrying 157 different variants with a supposed pathogenic effect were identified. Fifty-four variants have been described only in the Czech LGMD population so far. LGMD R1 caplain3-related is the most frequent subtype of LGMD involving 53.1% of patients with genetically confirmed LGMD, followed by LGMD R9 FKRP-related (11.1%), and LGMD R12 anoctamin5-related (7.1%). If we consider identified variants, then all but five were small-scale variants. One large gene deletion was identified in the LAMA2 gene and two deletions in each of CAPN3 and SGCG. We performed comparison our result with other published studies. The results obtained in the Czech LGMD population clearly differ from the outcome of other LGMD populations in two aspects-we have a more significant proportion of patients with LGMD R1 calpain3-related and a smaller proportion of LGMD R2 dysferlin-related.
ABSTRACT
Sudden cardiac death (SCD) might have an inherited cardiac condition background. Genetic testing supports post-mortem diagnosis and screening of relatives at risk. Our aim is to determine the feasibility of a Czech national collaboration group and to establish the clinical importance of molecular autopsy and family screening. From 2016 to 2021, we have evaluated 100 unrelated SCD cases (71.0% males, age: 33.3 (12.8) years). Genetic testing was performed by next-generation sequencing utilizing a panel of 100 genes related to inherited cardiac/aortic conditions and/or whole exome sequencing. According to autopsy, cases were divided into cardiomyopathies, sudden arrhythmic death syndrome, sudden unexplained death syndrome, and sudden aortic death. We identified pathogenic/likely pathogenic variants following ACMG/AMP recommendations in 22/100 (22.0%) of cases. Since poor DNA quality, we have performed indirect DNA testing in affected relatives or in healthy parents reaching a diagnostic genetic yield of 11/24 (45.8%) and 1/10 (10.0%), respectively. Cardiological and genetic screening disclose 83/301 (27.6%) relatives at risk of SCD. Genetic testing in affected relatives as starting material leads to a high diagnostic yield offering a valuable alternative when suitable material is not available. This is the first multidisciplinary/multicenter molecular autopsy study in the Czech Republic which supports the establishment of this type of diagnostic tests. A central coordinator and proper communication among centers are crucial for the success of a collaboration at a national level.
ABSTRACT
Kabuki syndrome is mainly caused by dominant de-novo pathogenic variants in the KMT2D and KDM6A genes. The clinical features of this syndrome are highly variable, making the diagnosis of Kabuki-like phenotypes difficult, even for experienced clinical geneticists. Herein we present molecular genetic findings of causal genetic variation using array comparative genome hybridization and a Mendeliome analysis, utilizing targeted exome analysis focusing on regions harboring rare disease-causing variants in Kabuki-like patients which remained KMT2D/KDM6A-negative. The aCGH analysis revealed a pathogenic CNV in the 14q11.2 region, while targeted exome sequencing revealed pathogenic variants in genes associated with intellectual disability (HUWE1, GRIN1), including a gene coding for mandibulofacial dysostosis with microcephaly (EFTUD2). Lower values of the MLL2-Kabuki phenotypic score are indicative of Kabuki-like phenotype (rather than true Kabuki syndrome), where aCGH and Mendeliome analyses have high diagnostic yield. Based on our findings we conclude that for new patients with Kabuki-like phenotypes it is possible to choose a specific molecular testing approach that has the highest detection rate for a given MLL2-Kabuki score, thus fostering more precise patient diagnosis and improved management in these genetically- and phenotypically heterogeneous clinical entities.
Subject(s)
Abnormalities, Multiple/genetics , Face/abnormalities , Genetic Heterogeneity , Genotype , Hematologic Diseases/genetics , Phenotype , Vestibular Diseases/genetics , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/physiopathology , Child , Child, Preschool , Chromosomes, Human, Pair 14 , Comparative Genomic Hybridization , DNA-Binding Proteins/genetics , Exome , Face/physiopathology , Female , Hematologic Diseases/diagnosis , Hematologic Diseases/physiopathology , High-Throughput Nucleotide Sequencing , Histone Demethylases/genetics , Humans , Intellectual Disability/genetics , Male , Mandibulofacial Dysostosis/genetics , Microcephaly/genetics , Neoplasm Proteins/genetics , Nerve Tissue Proteins/genetics , Nuclear Proteins/genetics , Peptide Elongation Factors/genetics , Receptors, N-Methyl-D-Aspartate/genetics , Ribonucleoprotein, U5 Small Nuclear/genetics , Tumor Suppressor Proteins/genetics , Ubiquitin-Protein Ligases/genetics , Vestibular Diseases/diagnosis , Vestibular Diseases/physiopathologyABSTRACT
Familiar Mediterranean fever (FMF) is a well defined autosomal recessive disease occurring mostly in Mediterranean regions. Here we present the experience from one center from Czech Republic, where we follow 4 families with patients with genetically proven FMF. Three out of these 4 families cluster to one limited region in Moravia, in the heart of Europe, without any linkage to Mediterranean origin. Furthermore, majority of these patients are heterozygots presenting with well defined typical clinical symptoms. Potential pseudodominant inheritance and/or epigenetic and environmental factors might influence clinical presentation of the disease.
