Ben Ayed, Ikhlas, Bouchaala, Wafa, Bouzid, Amal, Feki, Wiem, Souissi, Amal, Ben Nsir, Sihem, Ben Said, Mariem, Sammouda, Takwa, Majdoub, Fatma, kharrat, Ines, Kamoun, Fatma, Elloumi, Ines, Kamoun, Hassen, Tlili, Abdelaziz, Masmoudi, Saber, and Triki, Chahnez
Intellectual disability (ID) often co-occurs with other neurologic phenotypes making molecular diagnosis more challenging particularly in consanguineous populations with the co-segregation of more than one ID-related gene in some cases. In this study, we investigated the phenotype of three patients from a large Tunisian family with significant ID phenotypic variability and microcephaly and performed a clinical exome sequencing in two cases. We identified, within the first branch, a homozygous variant in the TRAPPC9 gene (p.Arg472Ter) in two cases presenting severe ID, absent speech, congenital/secondary microcephaly in addition to autistic features, supporting the implication of TRAPPC9 in the "secondary" autism spectrum disorders and congenital microcephaly. In the second branch, we identified a homozygous variant (p.Lys189ArgfsTer15) in the CDK5RAP2 gene associated with an heterozygous TRAPPC9 variant (p.Arg472Ter) in one case harbouring primary hereditary microcephaly (MCPH) associated with an inter-hypothalamic adhesion, mixed hearing loss, selective thinning in the retinal nerve fiber layer and parafoveal ganglion cell complex, and short stature. Our findings expand the spectrum of the recently reported neurosensorial abnormalities and revealed the variable phenotype expressivity of CDK5RAP2 defect. Our study highlights the complexity of the genetic background of microcephaly/ID and the efficiency of the exome sequencing to provide an accurate diagnosis and to improve the management and follow-up of such patients. • The diagnosis of intellectual disability is more challenging within families with complex consanguinity loops. • TRAPPC9 is associated with secondary Autism spectrum disorder and congenital microcephaly. • CDK5RAP2 is involved in the ocular and cochlear development, as well as the hypothalamic nuclear separation at the midline. • Selective thinning in retinal nerve fiber layer and parafoveal ganglion cell complex was added to CDK5RAP2 defect. [ABSTRACT FROM AUTHOR]