Genotype-Phenotype Correlation in Cri du Chat Patients Carrying One or Two Copies of the TRIO Gene

Cri du Chat syndrome (CdCS) results from a variable-sized deletion of the short arm of chromosome 5 (5p) and is characterized by marked phenotypic heterogeneity. Previous genotype–phenotype correlation studies have primarily focused on deletion size, an approach inherently limited by the large number of genes within the deletion. A gene-centered strategy may therefore offer a better framework for interpreting specific clinical features. Among candidate genes on 5p, TRIO plays a critical role in RAC1-mediated neurodevelopment; furthermore, in related neurodevelopmental disorders, loss-of-function variants are associated with microcephaly, whereas gain-of-function variants are associated with macrocephaly. Clinical, cytogenetic, and molecular data were retrieved from the main database of the Italian charity A.B.C. (Associazione Bambini Cri du Chat). Fifty-two patients, classified as carriers of one or two copies of the TRIO gene, were included based on the availability of head circumference (HC) measurements, developmental milestones (sitting, walking, and first words) data, and a CGH array. All data were analyzed in relation to TRIO allele dosage, deletion size, and sex. All patients showed a reduced HC compared with reference curves. However, HC measurements were consistently higher in patients carrying two TRIO alleles versus those carrying only one. Deletion size did not correlate with HC or developmental milestones. Patients with two TRIO alleles generally achieved motor and language milestones earlier, and some differences between males and females, suggested the possibility of sex-specific differences. These findings indicate that TRIO allele dosage might contribute to head size and developmental outcomes in CdCS independent of deletion size. A gene-centered approach could thus improve genotype–phenotype correlations in chromosomal disorders and highlight the importance of considering sex-specific effects in clinical and rehabilitative management.