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RNU4-2 Syndrome or Neurodevelopmental disorder with hypotonia, brain anomalies, distinctive facies, and absent language (NEDHAFA) is an inherited disorder caused by mutations in the human gene RNU4-2, which encodes an RNA component of the major spliceosome. It is characterized by hypotonia, global developmental delay, severely impaired intellectual development with poor or absent speech, delayed walking or inability to walk, feeding difficulties with poor overall growth, dysmorphic facial features, and brain anomalies, including ventriculomegaly and progressive white matter loss.^[1]^[2]^[3]^[4]

RNU4-2 Syndrome is one of the most prevalent monogenic neurodevelopmental disorders, with an estimated prevalence second only to Rett syndrome. It is a dominantly inherited genetic disorder caused by mutations in RNU4-2, a gene on chromosome 12, which encodes the small nuclear RNA (snRNA) U4, a component of the small nuclear ribonuculeoprotein (snRNP) U4. snRNP U4 is a component of the major spliceosome, a structure necessary for RNA splicing. Most cases of RNU4-2 Syndrome are explained by a 1-bp insertion (n.64_65insT, NR_003137.2), which is thought to disrupt the interactions of snRNA U4 with the snRNA U6, affecting the stability of the ACAGAGA loop of U6 sRNA which binds 5' splice sites and induces splicing after U4-U6 unwinding.^[1]^[2]

The genetic etiology of RNU4-2 Syndrome was first identified by the English statistician Daniel Greene working at the Icahn School of Medicine at Mount Sinai through the Bayesian analysis^[5] of data collected by Genomics England, with replication in the NIHR BioResource.^[2]^[6] It was subsequently discovered and published independently by Yuyang Chen of the University of Oxford.^[4]

References

^ ^a ^b "NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, BRAIN ANOMALIES, DISTINCTIVE FACIES, AND ABSENT LANGUAGE; NEDHAFA". OMIM. Retrieved 2024-07-11.
^ ^a ^b ^c Greene, Daniel; Thys, Chantal; Berry, Ian R; Jarvis, Joanna; Ortibus, Els; Mumford, Andrew D; Freson, Kathleen; Turro, Ernest (2024-05-31). "Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders". Nature Medicine. doi:10.1038/s41591-024-03085-5. PMID 38821540.
^ Schot, Rachel; Ferraro, Federico; Geeven, Geert; Diderich, Karin E M; Barakat, Tahsin Stefan (2024-06-11). "Re-analysis of whole genome sequencing ends a diagnostic odyssey: Case report of an RNU4-2 related neurodevelopmental disorder". Clinical Genetics. doi:10.1111/cge.14574. PMID 38859706.
^ ^a ^b Chen, Yuyang; et al. (2024-07-11). "De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome". Nature. doi:10.1038/s41586-024-07773-7. ISSN 1476-4687. PMID 38991538.
^ Greene, Daniel; Richardson, Sylvia; Turro, Ernest (2017-07-06). "A Fast Association Test for Identifying Pathogenic Variants Involved in Rare Diseases". American Journal of Human Genetics. 101 (1): 104–114. doi:10.1016/j.ajhg.2017.05.015. PMC 5501869. PMID 28669401.
^ Yuyang Chen and Daniel Greene (2024-05-31). Genomics England Research Seminar May 2024 - Yuyang Chen and Daniel Greene. YouTube. Retrieved 2024-07-12.

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 {{Short description|This describes a novel genetic syndrome}}
-''' ''RNU4-2'' Syndrome''' or '''Neurodevelopmental disorder with hypotonia, brain anomalies, distinctive facies, and absent language (NEDHAFA)''' is an inherited disorder caused by mutations in the human gene ''[[RNU4-2]]'', which encodes an [[RNA]] component of the major [[spliceosome]]. It is characterized by [[hypotonia]], [[global developmental delay]], severely impaired intellectual development with poor or absent speech, delayed walking or inability to walk, feeding difficulties with poor overall growth, dysmorphic facial features, and brain anomalies, including ventriculomegaly and progressive white matter loss.<ref name="omimRNU42">{{cite web|url=https://omim.org/entry/620851 |title=NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, BRAIN ANOMALIES, DISTINCTIVE FACIES, AND ABSENT LANGUAGE; NEDHAFA | website=OMIM | access-date=2024-07-11}}</ref><ref name="Greene2024">{{cite journal |last1=Greene |first1=Daniel |last2=Thys |first2=Chantal |last3=Berry |first3=Ian R |last4=Jarvis |first4=Joanna |last5=Ortibus |first5=Els |last6=Mumford |first6=Andrew D |last7=Freson |first7=Kathleen |last8=Turro |first8=Ernest |title=Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders |journal=Nature Medicine |date=2024-05-31|doi=10.1038/s41591-024-03085-5 |pmid=38821540}}</ref><ref name="Schot2024">{{cite journal |last1=Schot |first1=Rachel |last2=Ferraro |first2=Federico |last3=Geeven |first3=Geert |last4=Diderich |first4=Karin E M |last5=Barakat |first5=Tahsin Stefan |title=Re-analysis of whole genome sequencing ends a diagnostic odyssey: Case report of an RNU4-2 related neurodevelopmental disorder |journal=Clinical Genetics |date=2024-06-11 |doi=10.1111/cge.14574 |pmid=38859706}}</ref><ref name="Chen2024">
+''' ''RNU4-2'' Syndrome''' or '''Neurodevelopmental disorder with hypotonia, brain anomalies, distinctive facies, and absent language (NEDHAFA)''' is an inherited disorder caused by mutations in the human gene ''[[RNU4-2]]'', which encodes an [[RNA]] component of the major [[spliceosome]]. It is characterized by [[hypotonia]], [[global developmental delay]], severely impaired intellectual development with poor or absent speech, delayed walking or inability to walk, feeding difficulties with poor overall growth, [[dysmorphic]] facial features, and brain anomalies, including ventriculomegaly and progressive white matter loss.<ref name="omimRNU42">{{cite web|url=https://omim.org/entry/620851 |title=NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, BRAIN ANOMALIES, DISTINCTIVE FACIES, AND ABSENT LANGUAGE; NEDHAFA | website=OMIM | access-date=2024-07-11}}</ref><ref name="Greene2024">{{cite journal |last1=Greene |first1=Daniel |last2=Thys |first2=Chantal |last3=Berry |first3=Ian R |last4=Jarvis |first4=Joanna |last5=Ortibus |first5=Els |last6=Mumford |first6=Andrew D |last7=Freson |first7=Kathleen |last8=Turro |first8=Ernest |title=Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders |journal=Nature Medicine |date=2024-05-31|doi=10.1038/s41591-024-03085-5 |pmid=38821540}}</ref><ref name="Schot2024">{{cite journal |last1=Schot |first1=Rachel |last2=Ferraro |first2=Federico |last3=Geeven |first3=Geert |last4=Diderich |first4=Karin E M |last5=Barakat |first5=Tahsin Stefan |title=Re-analysis of whole genome sequencing ends a diagnostic odyssey: Case report of an RNU4-2 related neurodevelopmental disorder |journal=Clinical Genetics |date=2024-06-11 |doi=10.1111/cge.14574 |pmid=38859706}}</ref><ref name="Chen2024">
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Revision as of 17:04, 22 July 2024

References

Further reading