Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders

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 unrelat...

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Published inNature medicine Vol. 30; no. 8; pp. 2165 - 2169
Main Authors Greene, Daniel, Thys, Chantal, Berry, Ian R., Jarvis, Joanna, Ortibus, Els, Mumford, Andrew D., Freson, Kathleen, Turro, Ernest
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group US 01.08.2024
Nature Publishing Group
Subjects
631/208/2489/144
631/208/366
Association analysis
Biomedical and Life Sciences
Biomedicine
Brief Communication
Cancer Research
Critical components
Etiology
Genetic analysis
Genetic screening
Genomic analysis
Hypotonia
Infectious Diseases
Intellectual disabilities
Metabolic Diseases
Microencephaly
Molecular Medicine
Mutation
Neurodevelopmental disorders
Neurological diseases
Neurosciences
Seizures
snRNA
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Abstract 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. Mutations in a small noncoding gene called RNU4-2 are responsible for one of the most common neurodevelopmental disorders that is mediated by a single gene.
AbstractList 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.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.
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.
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. Mutations in a small noncoding gene called RNU4-2 are responsible for one of the most common neurodevelopmental disorders that is mediated by a single gene.
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.Mutations in a small noncoding gene called RNU4-2 are responsible for one of the most common neurodevelopmental disorders that is mediated by a single gene.
Author Mumford, Andrew D.
Thys, Chantal
Ortibus, Els
Berry, Ian R.
Freson, Kathleen
Turro, Ernest
Jarvis, Joanna
Greene, Daniel
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Snippet Most people with intellectual disability (ID) do not receive a molecular diagnosis following genetic testing. To identify new etiologies of ID, we performed a...
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SubjectTerms 631/208/2489/144
631/208/366
Association analysis
Biomedical and Life Sciences
Biomedicine
Brief Communication
Cancer Research
Critical components
Etiology
Genetic analysis
Genetic screening
Genomic analysis
Hypotonia
Infectious Diseases
Intellectual disabilities
Metabolic Diseases
Microencephaly
Molecular Medicine
Mutation
Neurodevelopmental disorders
Neurological diseases
Neurosciences
Seizures
snRNA
Title Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders
URI https://link.springer.com/article/10.1038/s41591-024-03085-5
https://www.ncbi.nlm.nih.gov/pubmed/38821540
https://www.proquest.com/docview/3094586390
https://www.proquest.com/docview/3063466649
https://pubmed.ncbi.nlm.nih.gov/PMC11333284
Volume 30
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