INTS13 – Intellectual Disability

This summary reviews the evidence supporting the association of INTS13 (HGNC:20174) with intellectual disability (MONDO_0001071). The association is primarily derived from multi‐patient studies in which copy number variations (CNVs) encompassing the 12p11.21–12p11.23 region were identified, and INTS13 emerged as a candidate gene particularly when considered with additional loss‐of‐function events. In one study, a cryptic 4.7 Mb deletion was detected along with further investigation in six additional subjects and a review of eight DECIPHER cases (PMID:37563198), thereby implicating INTS13 in the spectrum of intellectual disability phenotypes.

The overall clinical validity of the INTS13–intellectual disability association is rated as Moderate. Although multiple CNV cases (a total nearing 15 subjects when combining index and DECIPHER cases) support the dosage imbalance, and candidate loss‐of‐function point mutations have been reported, the segregation data remain limited (PMID:37034680). Consequently, despite supportive genetic findings, additional familial or functional studies would strengthen the overall claim.

Genetic evidence further substantiates the candidate role of INTS13. The dominant inheritance pattern suggested by de novo CNVs and loss‐of‐function events implicates haploinsufficiency as a plausible mechanism. A representative variant, c.295C>T (p.Gly40Ter), is a clear loss‐of‐function allele consistent with the notion that reduced INTS13 activity contributes to the intellectual disability phenotype (PMID:37563198). Although detailed segregation analysis is sparse, the consistency of the variant type with known disease mechanisms lends support to its clinical relevance.

Functional evidence supports the molecular plausibility underlying the association. Preliminary assays suggest that haploinsufficiency of INTS13 may disrupt the function of the Integrator complex, which is essential for proper RNA processing in the developing brain. Expression studies point to high-level expression of INTS13 in neural tissues, aligning with the observed neurodevelopmental deficits (PMID:37563198). This experimental concordance further reinforces the link between INTS13 loss-of-function and the intellectual disability phenotype.

In integrating both genetic and functional findings, the data indicate that INTS13 contributes to intellectual disability via a dosage-sensitive mechanism. While the current evidence is derived largely from case series and CNV studies with limited direct familial segregation, it provides an important basis for diagnostic consideration and future research. The identification of a canonical loss-of-function variant, alongside complementary functional insights, supports the clinical utility of including INTS13 in diagnostic gene panels for patients with intellectual disability.

Key take‑home sentence: The weight of CNV and loss‐of‐function evidence, in combination with supportive functional data, makes INTS13 a significant candidate gene for intellectual disability, meriting further investigation for diagnostic and therapeutic applications.

References

• Scientific Reports • 2023 • A cryptic microdeletion del(12)(p11.21p11.23) within an unbalanced translocation implicates new candidate loci for intellectual disability and Kallmann syndrome PMID:37563198
• PMID:37034680 • 2023 • Case report evidence supporting CNV‐driven candidate associations in neurodevelopmental disorders

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