Analysis of Cytogenetic Abnormalities in Iranian Patients with Syndromic Autism Spectrum Disorder: A Case Series

Objective Autism spectrum disorder is a heterogeneous neuropsychiatric group of pervasive development disorder, which is mostly diagnosed through the intricate behavioral phenotype. According to strong genetic involvement, detecting the chromosome regions and the key genes linked to autism can help to elucidate its etiology. The present study aims to investigate the value of cytogenetic analysis in syndromic autism as well as to find an association between autism and chromosome abnormalities. Materials & Methods Thirty-six autism patients from 30 families, diagnosed clinically with DSM-5 criteria, were recruited. The syndromic patients who had additional clinical features involving development delay, attention deficit, hyperactivity disorder, seizure, language, and intellectual impairment were selected due to elevating the detection rate. Cytogenetics analysis was performed using GTG banding on the patients' cultured fibroblasts. Moreover, array-comparative genomic hybridization was also performed for a patient with a de novo and novel variant.   Results Karyotype analysis in 36 syndromic autism patients detected chromosomal abnormalities in two (5.6%) families, including 46,XY,dup(15)(q11.1q11.2) and 46,XX,ins(7)(q11.1q21.3)dn. In the latter, array-comparative genomic hybridization detected three abnormalities on chromosome 7, including deletion and insertion on both arms; 46,XX,del(7)(q21.11q21.3),dup(7)(p11.2p14.1p12.3)dn. Conclusion We reported a novel and de novo cytogenetic abnormality on chromosome 7 in an Iranian patient diagnosed with syndromic autism. However, the detection rate in syndromic autism was low which implies that it cannot be utilized as the only diagnostic procedure

Broadening the phenotype and genotype spectrum of novel mutations in pontocerebellar hypoplasia with a comprehensive molecular literature review

Abstract Background Pontocerebellar hypoplasia is an umbrella term describing a heterogeneous group of prenatal neurodegenerative disorders mostly affecting the pons and cerebellum, with 17 types associated with 25 genes. However, some types of PCH lack sufficient information, which highlights the importance of investigating and introducing more cases to further elucidate the clinical, radiological, and biochemical features of these disorders. The aim of this study is to provide an in-depth review of PCH and to identify disease genes and their inheritance patterns in 12 distinct Iranian families with clinically confirmed PCH. Methods Cases included in this study were selected based on their phenotypic and genetic information available at the Center for Comprehensive Genetic Services. Whole-exome sequencing (WES) was used to discover the underlying genetic etiology of participants' problems, and Sanger sequencing was utilized to confirm any suspected alterations. We also conducted a comprehensive molecular literature review to outline the genetic features of the various subtypes of PCH. Results This study classified and described the underlying etiology of PCH into three categories based on the genes involved. Twelve patients also were included, eleven of whom were from consanguineous parents. Ten different variations in 8 genes were found, all of which related to different types of PCH. Six novel variations were reported, including SEPSECS, TSEN2, TSEN54, AMPD2, TOE1, and CLP1. Almost all patients presented with developmental delay, hypotonia, seizure, and microcephaly being common features. Strabismus and elevation in lactate levels in MR spectroscopy were novel phenotypes for the first time in PCH types 7 and 9. Conclusions This study merges previously documented phenotypes and genotypes with unique novel ones. Due to the diversity in PCH, we provided guidance for detecting and diagnosing these heterogeneous groups of disorders. Moreover, since certain critical conditions, such as spinal muscular atrophy, can be a differential diagnosis, providing cases with novel variations and clinical findings could further expand the genetic and clinical spectrum of these diseases and help in better diagnosis. Therefore, six novel genetic variants and novel clinical and paraclinical findings have been reported for the first time. Further studies are needed to elucidate the underlying mechanisms and potential therapeutic targets for PCH

Additional file 1 of Broadening the phenotype and genotype spectrum of novel mutations in pontocerebellar hypoplasia with a comprehensive molecular literature review

Additional file 1: Supplementary Figure 1. Flowchart of included cases in this study. Supplementary Figure 2. Variant filtering and pathogenicity evaluation algorithm. Supplementary Figure 3. Pedigree of included cases in this study. Pedigree a-k are cases 1-12, respectively. The proband is shown by an arrow in each pedigree. Circle and squares represent female and male, respectively. People with same color in each pedigree have same clinical manifestations. Supplementary Figure 4. The structure of protein [1] included in this study and the position of mutated amino acid. a) Structure of human nuclear RNA exosome (PDB: 6H25) [2]. EXOS3 is shown by an arrow and the position of Asp132 which is substituted with Ala in case 1 and 2 b) Structure human tRNA Splicing Endonuclease (TSEN) Complex (PDB: 7UXA) [3]. TSEN2 and TSEN54 are shown by arrows c) Structure of human holo SepSecS (PDB: 7L1T) [4] and the position of Cys70 and His425 which are substituted with Arg in case 4 and 5 d) Structure of AMP deaminase 2 (PDB: 8HUB)[5] and the position of Arg 620 which is substituted with Ser in case 8 e) Structure of CLP1(Swiss model: Q92989) [6] and the position of Leu262 which is substituted with Val in case 9 and Arg140 which is substituted with His in case 10 and 11 f) Structure of TBC1D23 N terminal domain (PDB: 6JL7) [7] and the position of Met 153 which is substituted with Thr in case 12

<i>BRAT1</i>-related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients

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