Novel Biallelic INTS1 Variants May Expand the Phenotypic Spectrum of INTS1-Related Disorders-Case Report and...

Background/Objectives: Neurodevelopmental disorders (NDDs) are genetically heterogeneous conditions with a complex molecular etiology involving numerous genes. Biallelic pathogenic variants in INTS1 cause a rare autosomal recessive NDD characterized by congenital cataracts, growth retardation, facial dysmorphism, and global developmental delay. To date, the clinical description of this disorder has been based solely on individual case reports, and its phenotypic spectrum remains incompletely defined. Methods: A 9-year-old female proband was evaluated for developmental delay, multiple congenital anomalies, and distinctive craniofacial features. Whole-exome sequencing (WES) was performed, followed by Sanger validation and segregation analysis. Variant pathogenicity was assessed using in silico prediction tools and 3D protein structural modeling. Results: Whole-exome sequencing identified two novel compound heterozygous missense variants in INTS1, c.1145G>A (p.Arg382Gln) and c.1195G>A (p.Gly399Ser), both located in exon 9. Segregation analysis showed that c.1145G>A was inherited from the father and c.1195G>A from the mother, and both variants are extremely rare in population databases. Conclusions: We report a patient carrying novel biallelic INTS1 variants, whose clinical presentation differs from previously reported cases, including those with milder phenotypes characterized by preserved speech development and absence of intellectual disability. This observation broadens the clinical spectrum of INTS1-related disease and underscores its phenotypic heterogeneity.