Disease-causing variants in INTS1 are predicted to result in loss of function and have demonstrated an autosomal recessive pattern of inheritance, with homozygous and compound heterozygous nonsense and missense variants. One homozygous variant, p.(Ser1874*), was recurrent in apparently unrelated individuals, but there has been no obvious phenotype genotype relationship. Targeted testing of parents is prudent to establish biallelic inheritance of the variants and sequencing of additional affected and unaffected siblings can also be performed for diagnostic purposes or for identification of carrier status. Pathogenic variants in INTS1 are thought to disrupt formation or folding of the INTS1 protein, the largest subunit of the integrator complex in humans, and thus to impair functioning of this complex. INTS1 is highly conserved and targeted disruption of Ints1 in mice results in embryonic lethality at the early blastocyst stage for embryos on some genetic backgrounds. These mice have increased levels of unprocessed, primary U2 small nuclear (sn)RNA, suggestive of aberrant snRNA processing due to impaired integrator complex function.
INTS1