A novel homozygous TPM1 mutation in familial pediatric hypertrophic cardiomyopathy and in silico screening of potential targeting drugs.

OBJECTIVE: Familial hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. While sarcomeric gene mutations explain many HCM cases, the genetic basis of about half of HCM cases remains elusive. Here we aimed to identify the gene causing HCM in a non-consanguineous Saudi Arabian family with affected family members and a history of sudden death. The impact of the identified mutation on protein structure and potential drug targets were evaluated in silico. MATERIALS AND METHODS: Triplets (two HCM subjects and one patent ductus arteriosus (PDA) case) and unaffected parents were screened by targeted next-generation sequencing (NGS) for 181 candidate cardiomyopathy genes. In silico structural and functional analyses, including protein modeling, structure prediction, drug screening, drug binding, and dynamic simulations were performed to explore the potential pathogenicity of the variant and to identify candidate drugs. RESULTS: A homozygous missense mutation in exon 1 of TMP1 (assembly GRCh37-chr15: 63340781; G>A) was identified in the triplets [two HCM and one patent ductus arteriosus (PDA)] that substituted glycine for arginine at codon 3 (p.Gly3Arg). The parents were heterozygous for the variant. The mutation was predicted to cause a significant and deleterious change in the TPM1 protein structure that slightly affected drug binding, stability, and conformation. In addition, we identified several putative TPM1-targeting drugs through structure-based in silico screening. CONCLUSIONS: TPM1 mutations are a common cause of HCM and other congenital heart defects. To date, TPM1 has not been associated with isolated PDA; to our knowledge, this is the first report of the homozygous missense variation p.Gly3Arg in TPM1 associated with familial autosomal recessive pediatric HCM and PDA. The identified candidate TPM1 inhibitors warrant further prospective investigation.

Next-generation sequencing identifies a homozygous mutation in ACADVL associated with pediatric familial dilated cardiomyopathy.

OBJECTIVE: Pediatric familial dilated cardiomyopathy (DCM) is a rare and severe heart disease. The genetics of familial DCM are complex and include over 100 known disease-causing genes, but many causative genes are unknown. We aimed to identify the causative gene for DCM in a consanguineous Saudi Arabian family with affected family members and a history of sudden death. PATIENTS AND METHODS: Affected (two children) and unaffected (one sibling and the mother) family members were screened by next-generation sequencing (NGS) for 181 candidate DCM genes and underwent metabolic screening. Fifty-seven clinically annotated controls and 46 DCM cases were then tested for the identified mutation. In silico structural and functional analyses including protein modeling, structure prediction and dynamic simulations were performed. RESULTS: A homozygous missense mutation in exon 15 of the acyl-CoA dehydrogenase very long chain gene (ACADVL; chr17:7127303; G>A) was identified in affected subjects that substituted histidine for arginine at codon 450 (p.R450H). The variant was heterozygous in the mother and unaffected sister. The mutation was absent in 57 clinically annotated controls and 48 pediatric DCM cases. The mutation was predicted to cause a significant and deleterious change in the ACADVL protein structure that affected drug binding, stability, and conformation. Metabolic screening confirmed VLCAD deficiency in affected individuals. CONCLUSIONS: The ACADVL R450H mutation is an uncommon cause of the DCM phenotype that appears to be autosomal recessive. Targeted NGS is useful for identifying the causative mutation(s) in familial DCM of unknown genetic cause.