Diagnostic yield of whole-exome sequencing in non-syndromic intellectual disability.

BACKGROUND: Aetiological diagnosis in non-syndromic intellectual disability (NSID) still poses a diagnostic challenge to clinicians. METHODS: Screening is currently achieved by chromosomal microarrays followed by whole-exome sequencing (WES). In search for the aetiological yield of WES in patients with NSID, 59 unrelated patients were studied. RESULTS: Among the 59 patients, 44 (74.6%) were from consanguineous unions. Epilepsy was present in 11 (37.9%), behavioural problems in 12 (41.4%) and autistic features in 14 (48.3%). WES analysis resulted in molecular diagnosis in 29 patients (49.2%). Some of the genes were specific for nervous system functioning, like HERC1, TBC1D7, LINS, HECW2, DEAF1, HNMT, DLG3, NRXN1 and HUWE1. Others were ubiquitously expressed genes involved in fundamental cellular processes, like IARS, UBE3A, COQ4, TAF1, SETBP1, ARV1, ZC4H2, KAT6A, ASXL3, THOC6, HNRNPH2, TUBA8 and KIF1A. Twenty-two (75.8%) were consanguineously married; however, only 12 (41.4%) of the detected genes caused autosomal recessive phenotypes. CONCLUSIONS: This cohort suggests that recessive genes probably represent an actually smaller subgroup of NSID, even among families with consanguinity. Although in societies with high consanguinity rates, considering the recessive inheritance first seems to be an advantageous strategy, de novo mutations in autosomal dominantly expressed genes represent the major aetiological group in patients with NSID, even among those patients from consanguineous families.

Genetic IGF1R defects: new cases expand the spectrum of clinical features.

PURPOSE: We aimed to identify the phenotypic variability of IGF1R defects in a cohort of short children with normal GH secretion gathered through the last decade. PATIENTS AND METHODS: Fifty children (25 girls) with short stature and a basal/stimulated growth hormone (GH) over 10 ng/ml having either a low birth weight or microcephaly were enrolled. MLPA and then Sanger sequence analysis were performed to detect IGF1R defects. The auxological and metabolic evaluation were carried out in index cases and their first degree family members whenever available. RESULTS: A total of seven (14%) IGF1R defects were detected. Two IGF1R deletions and five heterozygous variants (one frameshift, four missense) were identified. Three (likely) pathogenic, one VUS and one likely benign were classified by using ACMG. All children with IGF1R defects had a height < - 2.5SDS, birth weight < - 1.4SDS, and head circumference < - 1.36SDS. IGF-1 ranged from - 2.44 to 2.13 SDS. One child with a 15q terminal deletion had a normal phenotype and intelligence, whereas low IQ is a finding in a case with missense variant. Two parents who carried IGF1R mutations had diabetes mellitus, hypertension and hyperlipidemia, one of whom also had hypergonadotropic hypogonadism. CONCLUSION: We found a deletion or variant in IGF1R in 14% of short children. Birth weight, head circumference, intelligence, dysmorphic features, IGF-1 levels and even height are not consistent among patients. Additionally, metabolic and gonadal complications may appear during adulthood, suggesting that patients should be followed into adulthood to monitor for these late complications.