Table_1_Rare Case of Ulnar-Mammary-Like Syndrome With Left Ventricular Tachycardia and Lack of TBX3 Mutation.XLSX

<p>“Heart–hand” type syndromes represent a group of rare congenital conditions that combine cardiac pathology (structural defect or arrhythmic disorder) and limb abnormality. Significant clinical variability and genetic heterogeneity typical for such syndromes complicate correct diagnosis, prognosis, and appropriate genetic counseling of the affected families. By now, only single genes have been unambiguously determined as a genetic cause of heart–hand syndromes and phenotypically similar conditions. In the present study, we report on a 25-year-old Russian female patient with a clinical picture resembling ulnar-mammary syndrome (UMS). Principal clinical manifestations included heart septal fibrosis and non-sustained left ventricular tachycardia combined with fifth finger camptodactyly, hypoplastic breast, abnormal teeth, and mental retardation. Target Sanger sequencing and array-based comparative genome hybridization confirmed the lack of pathogenic mutations and large-scale deletions in TBX3 (12q24.21), the only gene known to be associated with UMS cases to date. Based on the results of whole-exome sequencing, 14 potential candidate variants were identified. Among them, a novel missense variant in SYNM gene (exon 1, c.173C > T, p.A58V), encoding intermediate filament protein synemin was characterized. Until the present, no association between SYNM mutations and congenital clinical syndromes has been reported. At the same time, taking into account synemin tissue-specific expression profiles and available data on abnormal knock-out mice phenotypes, we propose SYNM as a candidate gene contributing to the UMS-like phenotype. Further comprehensive functional studies are required to evaluate possible involvement of SYNM in genesis of complex heart-limb pathology.</p

Image_1_Rare Case of Ulnar-Mammary-Like Syndrome With Left Ventricular Tachycardia and Lack of TBX3 Mutation.TIF

<p>“Heart–hand” type syndromes represent a group of rare congenital conditions that combine cardiac pathology (structural defect or arrhythmic disorder) and limb abnormality. Significant clinical variability and genetic heterogeneity typical for such syndromes complicate correct diagnosis, prognosis, and appropriate genetic counseling of the affected families. By now, only single genes have been unambiguously determined as a genetic cause of heart–hand syndromes and phenotypically similar conditions. In the present study, we report on a 25-year-old Russian female patient with a clinical picture resembling ulnar-mammary syndrome (UMS). Principal clinical manifestations included heart septal fibrosis and non-sustained left ventricular tachycardia combined with fifth finger camptodactyly, hypoplastic breast, abnormal teeth, and mental retardation. Target Sanger sequencing and array-based comparative genome hybridization confirmed the lack of pathogenic mutations and large-scale deletions in TBX3 (12q24.21), the only gene known to be associated with UMS cases to date. Based on the results of whole-exome sequencing, 14 potential candidate variants were identified. Among them, a novel missense variant in SYNM gene (exon 1, c.173C > T, p.A58V), encoding intermediate filament protein synemin was characterized. Until the present, no association between SYNM mutations and congenital clinical syndromes has been reported. At the same time, taking into account synemin tissue-specific expression profiles and available data on abnormal knock-out mice phenotypes, we propose SYNM as a candidate gene contributing to the UMS-like phenotype. Further comprehensive functional studies are required to evaluate possible involvement of SYNM in genesis of complex heart-limb pathology.</p

Additional file 2: of Ring chromosome 18 in combination with 18q12.1 (DTNA) interstitial microdeletion in a patient with multiple congenital defects

Confirmation of DTNA deletion in the patient using quantitative real-time PCR analysis (qPCR). Description of data: qPCR data revealed one copy of the DTNA gene (18q12.1) in a patient DNA sample as compared to two copies of the gene in a normal control DNA sample. The data was normalized against GAPDH gene using the comparative ΔΔCt method. RQ (relative quantity) value is presented along the vertical axis. Each reaction was reproduced (repeated) in triplicate for both DNA samples (patient and control) and both genes (DTNA and GAPDH). The series of four ten-fold dilutions were included into analysis with the starting amount of DNA ~ 1 ng. The results obtained for one of the dilutions are depicted in the figure; for the rest dilutions, the ratio of quantity values between test and control samples was the same. (PNG 8 kb

Interaction network of proteins harboring RCM-associated genetic variants.

<p>For proteins with RCM-associated pathogenic and likely pathogenic variants (red boxed), variants of unknown significance (orange boxes) and rare SNPs (yellow boxes) a closely interconnected network was generated by manual curation of scientific literature. The interlinking proteins are shown as gray boxes. Green arrows, red lines with cross bars, green lines with filled circles, and blue lines indicate activation, inhibition, modulation of activity, and direct physical interactions, respectively.</p