Hamidreza Khodadadi

Spastic paraplegia 50 (SPG50) is a rare autosomal recessive disorder caused by mutations in the AP4M1 gene (OMIM 602296). It is characterized by spasticity, severe intellectual disability, and delayed or absent speech. The present study reported a case from consanguineous parents, where the affected child presented with intellectual disability, seizures, muscle weakness, and deep white matter hyperintensity. Whole exome sequencing (WES) of the proband identified a novel, homozygous frameshift variant, c.258delG:p.A87Pfs*44, in the AP4M1 gene, which was confirmed by Sanger sequencing. This variant is predicted to cause a large truncation of the protein, leading to a loss of function. Molecular modeling and docking analyses further revealed that the loss of a substantial protein segment disrupts proper intramolecular interactions. A review of the literature on Iranian families with SPG50 yielded few reports, consistent with the disease’s rarity. This study expanded the knowledge of the clinical and genetic features of SPG50 and underscored the importance of this variant for genetic diagnosis and counseling in affected families.

Cerebral palsy (CP) is a neurodevelopmental disorder of motor function, with genetic etiologies, particularly de novo variants, identified in approximately one-third of cases. The contribution of consanguinity – long-recognized as a CP risk factor – has remained undefined. Here, we report findings from 188 primarily consanguineous Middle Eastern families with CP and identified putative causative genes in nearly three-quarters. The majority demonstrated recessive inheritance, although multi-level consanguinity and multilocus pathogenic variants complicated Mendelian assortment analyses. We identified 110 known CP-associated genes – five with phenotypic expansions and three others exhibiting new recessive inheritance patterns – and 24 novel candidates. We characterized ten candidates as high-confidence based on independent replication and protein modeling. We experimentally validated a role for SUCO variants in CP and newly identified a role for mid-gestational migrating excitatory neurons in the disorder. These findings highlight new genes, pathways, and phenotypes that reveal striking genomic diversity in CP.

Introduction: Hypomyelinating leukodystrophy-5 (HLD-5) is a rare multiple congenital anomaly with intellectual disability caused by an autosomal recessive mutation in the FAM126A gene. It is characterized by bilateral congenital cataracts, developmental delay, cerebellar ataxia, slowly progressive gait disturbance, and cognitive impairment. This study aims to contribute to a better understanding of HLD-5 ...

Background and objective Mutations in the KAT6A gene, which encodes a histone acetyltransferase, have been linked to an autosomal dominant neurodevelopmental disorder known as the Arboleda-Tham syndrome. The clinical symptoms of this disorder are nonspecific and pose challenges to accurately characterizing the condition based solely on these symptoms. This study aimed to establish a definitive diagnosis in three patients with intellectual disability and multiple congenital anomalies, and to elucidate the genotype-phenotype correlation based on the existing literature. Participants and methods In this study, we investigated three probands with severe intellectual disability, global developmental delay, hypotonia, gait disturbance, microcephaly, scoliosis, abnormal heart morphology, strabismus, gastrointestinal dysmotility, and abnormal facial shape, using karyotype analysis, multiplex ligation-dependent probe amplification, and whole exome sequencing. We also conducted a comprehensive literature review of previously reported cases. Results The karyotype analysis and Multiplex ligation-dependent probe amplification results were normal. Whole exome sequencing revealed three novel de novo mutations, c.3712G > T (p.Glu1238*), c.3561 C > A (p.Cys1187*), and c.1069 C > T (p.Arg357*), in the KAT6A gene (NM_006766.5). The heterozygous variants were verified by Sanger sequencing and were not present in either parent. Conclusions In this study, we describe three cases of de novo KAT6A variants that were identified for the first time in Iran. Our results expand the understanding of the clinical features associated with Arboleda-Tham syndrome and validate the effectiveness of whole-exome sequencing to rapidly and accurately determine the etiology of such disorders. Furthermore, our literature review demonstrated close genotype-phenotype correlations associated with KAT6A and Arboleda-Tham syndrome.

We herein report first Iranian families with spastic paraplegia 35 and 49 and claim that TECPR2 gene causes complicated spastic paraplegia 49 with or without sensory autonomic neuropathy. In addition, we show how coexistence of SPG49 and griscelli syndrome can lead to misdiagnosis.