Investigação genética de deficiência intelectual recorrente em família do sertão de Alagoas

Abstract

Intellectual disability is a condition characterized by behavioral and cognitive alterations, which can be clinically syndromic or non-syndromic. Its global prevalence is estimated to be between 1% and 3%, being more frequent in males. Due to its high etiological and clinical heterogeneity, elucidating its causes is challenging. In this context, the present study aimed to conduct a molecular investigation into the cause of recurrent intellectual disability in men from a family originating from the city of Piranhas, in the hinterlands of Alagoas, Brazil. The investigated family nucleus consists of a couple with eight offspring, two women and six men, four of whom present severe intellectual disability associated with other clinical manifestations such as delusional psychiatric disorder, hetero-aggressiveness, and macrocephaly. The mother also has moderate intellectual disability. For molecular investigation, biological samples were collected from five family members (father, mother, daughter, and two sons with the condition in question). Initially, based on family history and clinical presentation, analysis focused on the FMR1 gene, associated with Fragile X syndrome -the most common monogenic cause of intellectual disability with X-linked dominant inheritance. After a negative results for Fragile X whole-exome sequencing was performed on one individual with the clinical phenotype, followed by familial co-segregation analysis using Sanger sequencing. This approach led to the identification of a novel nonsense variant in hemizygosity (c.262C>T; p.Arg88*) in the SYP gene (Synaptophysin, NM_003179.3), located at Xp11.23. This variant introduces a premature stop codon, leading to the interruption of protein synthesis. The SYP gene encodes synaptophysin, a 313-amino acid integral membrane protein that is highly conserved among mammals. Synaptophysin plays a key role in synaptic vesicle endocytosis and is considered the most abundant synaptic vesicle protein.Pathogenic variants in the SYP gene have previously been associated with X-linked intellectual disability, frequently accompanied by epilepsy. In this context, the clinical characteristics evidenced in the present study have already been reported in the literature in relation to alterations in the SYP gene. However, in addition to the cited clinical signs, all affected male individuals evaluated present macrocephaly and psychiatric disorders, expanding the spectrum of clinical phenotype associated with the new variant in the SYP gene.