Most people with intellectual disability (ID) do not receive a molecular
diagnosis following genetic testing. To identify new etiologies of ID, we
performed a genetic association analysis comparing the burden of rare
variants in 41,132 noncoding genes between 5,529 unrelated cases and 46,401
unrelated controls. RNU4-2, which encodes U4 small nuclear RNA, a critical
component of the spliceosome, was the most strongly associated gene. We
implicated de novo variants among 47 cases in two regions of RNU4-2 in the
etiology of a syndrome characterized by ID, microcephaly, short stature,
hypotonia, seizures and motor delay. We replicated this finding in three
collections, bringing the number of unrelated cases to 73. Analysis of
national genomic diagnostic data showed RNU4-2 to be a more common
etiological gene for neurodevelopmental abnormality than any previously
reported autosomal gene. Our findings add to the growing evidence of
spliceosome dysfunction in the etiologies of neurological disorders.