Biallelic, deleterious variants in the INTS1 gene are rare. To date, 10 patients have been reported in the medical literature, although it is possible that the condition will be better delineated in the future. Frequent findings in affected individuals have included neurocognitive differences and multiple congenital anomalies.
Patients have had delayed expressive language, low muscle tone, gait abnormalities and magnetic resonance imaging (MRI) of the brain has shown anomalies affecting the corpus callosum and cerebellum. Eye findings have included early onset of cataracts together with strabismus and refractive errors. Facial anomalies have comprised wide-spaced eyes that can be deep-set, a wide nasal bridge and a short nose with a broad tip, low-set ears with anomalous helices, an abnormal dentition with a wide diastema, and downturned corners of the mouth. Other clinical findings have included pectus deformities, short neck, overlapping toes and renal anomalies.
Inheritance of pathogenic INTS1 variants is autosomal recessive and loss of function has been predicted for the variants. Missense and nonsense variants have been noted and there is no clear phenotype genotype correlation. The gene encodes the largest subunit of the integrator complex and the variants are thought to impair complex function, resulting in abnormal processing of small nuclear RNAs, although the pathogenic mechanism is not well understood.
INTS1