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Background and Aims: Congenital heart defects (CHD) are the most common type of congenital disability. Copy number variations (CNVs) have been found as one of the genetic etiology of non-syndromic CHD, and researchers have detected several pathogenic CNVs in patients with cardiac defects. Materials and Methods: In the present study, 70 patients with familial (20 patients) and sporadic (50 patients) non-syndromic CHD were evaluated to find whether CNVs in the GATA4, NKX2-5, TBX-5, CREL, BMP4 genes, and 22q11.2 region contribute to the pathogenesis of non-syndromic CHD. We have used the Multiplex Ligation-dependent Probe Amplification (MLPA) technique as a molecular method to identify CNVs in predefined loci. Results: Normal MLPA results were demonstrated for GATA4, NKX2-5, TBX-5, CRELD, and BMP4 genes for all sporadic and familial cases. However, we found three patients with imbalances for the 22q11.2 region. One patient with 22q11.2 deletion showed tetralogy of fallot, and the other had ventricular septal defects/ pulmonary atresia/ multiple aortopulmonary collateral arteries. A duplication of the 22q11.2 region was detected in one patient with patent ductus arteriosus. Conclusion: Identifying genomic imbalances in 6% of the non-syndromic sporadic patients indicates that recurrent CNVs could be associated with non-syndromic CHD. It seems that it is the first CNV analysis using MLPA carried out in Iranian patients with cardiac defects. We suggest that 22q11.2 imbalances should be considered in patients with cardiac lesions to provide an accurate diagnosis and appropriate genetic counseling in affected families.

Homozygous mutations of ALDH5A1 have been reportedly associated with Succinic semialdehyde dehydrogenase deficiency (SSADHD) that affects gamma-aminobutyric acid (GABA) catabolism and evinces a wide range of clinical phenotype from mild intellectual disability to severe neurodegenerative disorders. We report clinical and molecular data of a Lor family with 2 affected members presenting with severe intellectual disability, developmental delay, and generalized tonic-clonic seizures. A comprehensive genetic study that included whole-exome sequencing identified a homozygous missense substitution (NM_001080:c.G1321A:p.G441R) in ALDH5A1 (Aldehyde Dehydrogenase 5 Family Member A1) gene, consistent with clinical phenotype in the patients and co-segregating with the disease in the family. The non-synonymous mutation, p.G441R, affects a highly conserved amino acid residue, which is expected to cause a severe destabilization of the enzyme. Protein modeling demonstrated an impairment of the succinic semialdehyde (SSA) binding tunnel accessibility, and the anticipation of the protein folding stability and dynamics was a decrease in the free energy by 4.02 kcal/mol. Consistent with these in silico findings, excessive γ -hydroxybutyrate (GHB) could be detected in patients' urine as the byproduct of the GABA pathway. SSADHD, Succinic semialdehyde dehydrogenase deficiency; GABA, gamma-aminobutyric acid; ALDH5A1, Aldehyde Dehydrogenase 5 Family Member A1; GHB, γ -hydroxybutyrate; SSA, succinic semi aldehyde; WISC, Wechsler Intelligence Scale for Children; CNS, central nervous system ; EEG, electroencephalography; EEEF, empirical effective energy functions; ASD, autism spectrum disorder; ADHD, attention deficit hyperactivity disorder; IQ, intelligence quotient; EMG, electromyography; NCV, nerve conduction velocity; CP, cerebral palsy.

Autism spectrum disorder (ASD) is characterized by 3 core symptoms with impaired social communication, repetitive behavior, and/or restricted interests in early childhood. As a complex neurodevelopmental disorder (NDD), the phenotype and severity of autism are extremely heterogeneous. Genetic factors have a key role in the etiology of autism. In this study, we investigated an Azeri Turkish family with 2 ASD-affected individuals to identify probable ASD-causing variants. First, the affected individuals were karyotyped in order to exclude chromosomal abnormalities. Then, whole-exome sequencing was carried out in one affected sibling followed by cosegregation analysis for the candidate variants in the family. In addition, SNP genotyping was carried out in the patients to identify possible homozygosity regions. Both proband and sibling had a normal karyotype. We detected 3 possible causative variants in this family: c.5443G>A; p.Gly1815Ser, c.1027C>T; p.Arg343Trp, and c.382A>G; p.Lys128Glu, which are in the FBN1, TF, and PLOD2 genes, respectively. All of the variants cosegregated in the family, and SNP genotyping revealed that these 3 variants are located in the homozygosity regions. This family serves as an example of a multimodal polygenic risk for a complex developmental disorder. Of these 3 genes, confluence of the variants in FBN1 and PLOD2 may contribute to the autistic features of the patient in addition to skeletal problems. Our study highlights the genetic complexity and heterogeneity of NDDs such as autism. In other words, in some patients with ASD, multiple rare variants in different loci rather than a monogenic state may contribute to the development of phenotypes.

Recent achievements in the genetic diagnosis of Dilated Cardiomyopathy (DCM) have disclosed rare variants in numerous genes encoding different types of myocardial proteins. However, the causative gene underlying the pathogenesis of about 60% of familial cases with DCM has not been identified. One novel gene introduced in 2016 for cardiac-restricted DCM is FLNC. In this study, we applied Whole Exome Sequencing (WES) and bioinformatics-based methods to a member of an extended non-consanguineous family with DCM history accompanied with fatal arrhythmia in at least four consecutive generations. We found a novel splice-site mutation in FLNC gene (c.2389+1G>A) which cosegregated with all symptomatic individuals in the family. Computational prediction software tools as well as RT-PCR method were used to evaluate the impact of the FLNC splice site mutation. This substitution leads to exon 15th donor-site disruption and exon skipping, which would result in a premature stop codon three aminocids downstream of the mutation site. The aberrantly mRNA transcript can induce nonsense-mediated mRNA decay. Although carrier individuals show remarkable variable expression regarding the severity of DCM as well as the disease age of onset, a highly penetrant fatal arrhythmia was found to be shared between them. We strongly suggest that the involvement of FLNC gene, due to haploinsufficiency, should be considered in familial cases with DCM, especially if accompanied with arrhythmia and increased incidence of sudden cardiac death.