Diagnostic yield of whole-exome sequencing in non-syndromic intellectual disability.
One blood test gives a firm genetic answer in half of non-syndromic ID cases, even when parents are cousins.
01Research in Context
What this study did
Doctors sequenced every gene in the kids who had intellectual disability with no known syndrome.
Half of the families were related by blood, so the team expected to find recessive genes.
They used whole-exome sequencing, a lab test that reads the protein-making parts of DNA.
What they found
A clear genetic cause showed up in 49 out of the children.
Most causes were new, one-time mutations, even in the inbred families.
Recessive genes appeared less often than the doctors first guessed.
How this fits with other research
Arcebido et al. (2025) looked at real-world clinics and saw only 31 % of patients ever get any genetic test.
Z et al. found answers in half of cases, but Kyla shows most families never reach the lab, so the real help rate is lower.
Evans et al. (1994) cut open 60 brains and listed physical defects; Z et al. now give a live molecular map of the same group, updating the picture without needing autopsy.
Why it matters
You can now tell parents there is a 50-50 shot of finding a cause with one blood test.
If the test is negative, you still save years of guessing.
Push for the test early, especially before starting costly metabolic work-ups.
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02At a glance
03Original abstract
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.
Journal of intellectual disability research : JIDR, 2021 · doi:10.1111/jir.12835