Unveiling New Clinical and Genetic Insights in Ultra‐Rare Intellectual Disability Phenotypes: A Study of a Turkish Cohort

ABSTRACT Intellectual disability (ID) is defined as a severe impairment in reasoning, learning, and problem‐solving abilities along with adaptive behavior that occurs before the age of 18 years. The present study aimed to present the clinical and genetic data of a cohort of Turkish pediatric patients diagnosed with the ultrarare (which only up to 20 cases having been reported in the relevant literature thus far) ID phenotype. A total of 29 patients from 26 different families, who were diagnosed with ultrarare ID upon whole exome sequencing (WES) analysis, were included in the study. Of the patients included in the study, 18 (62%) were male and 11 (38%) were female. There was consanguinity between parents in 16 families (55%). With respect to the ID phenotype, three families had cases with a similar phenotype, while 23 families (88%) had sporadic cases. Upon molecular analysis, 28 different variations in 23 different genes were noted. Of the variations detected, 15 were missense, 6 nonsense, 4 frameshift, 2 splice‐site, and 1 gross exonic deletion. Nine (32%) variations were novel among the detected variations. This study summarized the clinical and genetic features of 23 different ultrarare ID phenotypes by means of WES study, including copy number variations (CNVs) analysis. Novel clinical and genetic findings in the present study contribute to a better understanding of the genotypic and phenotypic spectrum. The effects of some rare variations on protein structure were revealed by means of in silico modeling. Newly described cases with ultrarare phenotypes help achieve a clearer description of the clinical and genetic manifestations of the syndromes and gain a better understanding of the molecular mechanisms.