Authors: Fakir Zineb , Bouzroud Wafaa , Berrada Sarah , Tazzite Amal , Gazzaz Bouchaib , Dehbi Hind

Abstract

Background : TRRAP-related neurodevelopmental disorder is a rare and incompletely characterized condition. Additional cases are needed to refine its clinical spectrum, especially in patients carrying non-missense variants. We report two unrelated adult Moroccan women with heterozygous TRRAP variants, including one previously unreported frameshift variant.

Case presentation : The first patient was a 21-year-old woman with syndromic intellectual disability, attention-deficit/hyperactivity disorder, facial dysmorphism, digital anomalies, white matter abnormalities, hydronephrosis in a malrotated kidney, and a bicornuate bicervical uterus. Whole exome sequencing identified a novel heterozygous TRRAP frameshift variant, c.4796dup, p.(Leu1599PhefsTer63). The second patient was a 30-year-old woman with syndromic intellectual disability, epilepsy beginning at 14 months of age, congenital atrial and ventricular septal defects, facial dysmorphism, and mild ventriculomegaly. Initial exome analysis was non-diagnostic, but reanalysis two years later identified a heterozygous TRRAP missense variant, c.2686G>A, p.(Gly896Ser).

Conclusion :  These cases contribute to the phenotypic and molecular spectrum of TRRAP-related neurodevelopmental disorder and support marked clinical heterogeneity, with overlap between neurodevelopmental, epileptic, and multisystem malformative presentations. The first case suggests that truncating variants outside the previously emphasized missense region may also be associated with multisystem disease, while the second highlights the diagnostic value of exome reanalysis in unresolved syndromic intellectual disability.

Keywords: TRRAP, neurodevelopmental disorder, frameshift, whole exome sequencing, intellectual disability, case report.