TY - JOUR
T1 - H4C5 missense variant leads to a neurodevelopmental phenotype overlapping with Angelman syndrome
AU - Undiagnosed Diseases Network
AU - Borja, Nicholas
AU - Borjas-Mendoza, Paulo
AU - Bivona, Stephanie
AU - Peart, LéShon
AU - Gonzalez, Joanna
AU - Johnson, Brittney Keira
AU - Guo, Shengru
AU - Yusupov, Roman
AU - Acosta, Maria T.
AU - Adam, Margaret
AU - Adams, David R.
AU - Agrawal, Pankaj B.
AU - Alejandro, Mercedes E.
AU - Alvey, Justin
AU - Amendola, Laura
AU - Andrews, Ashley
AU - Ashley, Euan A.
AU - Azamian, Mahshid S.
AU - Bacino, Carlos A.
AU - Bademci, Guney
AU - Baker, Eva
AU - Balasubramanyam, Ashok
AU - Baldridge, Dustin
AU - Bale, Jim
AU - Bamshad, Michael
AU - Barbouth, Deborah
AU - Bayrak-Toydemir, Pinar
AU - Beck, Anita
AU - Beggs, Alan H.
AU - Behrens, Edward
AU - Bejerano, Gill
AU - Bennet, Jimmy
AU - Berg-Rood, Beverly
AU - Bernstein, Jonathan A.
AU - Berry, Gerard T.
AU - Bican, Anna
AU - Bivona, Stephanie
AU - Blue, Elizabeth
AU - Bohnsack, John
AU - Bonnenmann, Carsten
AU - Bonner, Devon
AU - Botto, Lorenzo
AU - Boyd, Brenna
AU - Briere, Lauren C.
AU - Brokamp, Elly
AU - Dasari, Surendra
AU - Lanpher, Brendan C.
AU - Lanza, Ian R.
AU - Morava, Eva
AU - Oglesbee, Devin
N1 - Publisher Copyright:
© 2023 Wiley Periodicals LLC.
PY - 2023/7
Y1 - 2023/7
N2 - Recurrent de novo missense variants in H4 histone genes have recently been associated with a novel neurodevelopmental syndrome that is characterized by intellectual disability and developmental delay as well as more variable findings that include short stature, microcephaly, and facial dysmorphisms. A 4-year-old male with autism, developmental delay, microcephaly, and a happy demeanor underwent evaluation through the Undiagnosed Disease Network. He was clinically suspected to have Angelman syndrome; however, molecular testing was negative. Genome sequencing identified the H4 histone gene variant H4C5 NM_003545.4: c.295T>C, p.Tyr99His, which parental testing confirmed to be de novo. The variant met criteria for a likely pathogenic classification and is one of the seven known disease-causing missense variants in H4C5. A comparison of our proband's findings to the initial description of the H4-associated neurodevelopmental syndrome demonstrates that his phenotype closely matches the spectrum of those reported among the 29 affected individuals. As such, this report corroborates the delineation of neurodevelopmental syndrome caused by de novo missense H4 gene variants. Moreover, it suggests that cases of clinically suspected Angelman syndrome without molecular confirmation should undergo exome or genome sequencing, as novel neurodevelopmental syndromes with phenotypes overlapping with Angelman continue to be discovered.
AB - Recurrent de novo missense variants in H4 histone genes have recently been associated with a novel neurodevelopmental syndrome that is characterized by intellectual disability and developmental delay as well as more variable findings that include short stature, microcephaly, and facial dysmorphisms. A 4-year-old male with autism, developmental delay, microcephaly, and a happy demeanor underwent evaluation through the Undiagnosed Disease Network. He was clinically suspected to have Angelman syndrome; however, molecular testing was negative. Genome sequencing identified the H4 histone gene variant H4C5 NM_003545.4: c.295T>C, p.Tyr99His, which parental testing confirmed to be de novo. The variant met criteria for a likely pathogenic classification and is one of the seven known disease-causing missense variants in H4C5. A comparison of our proband's findings to the initial description of the H4-associated neurodevelopmental syndrome demonstrates that his phenotype closely matches the spectrum of those reported among the 29 affected individuals. As such, this report corroborates the delineation of neurodevelopmental syndrome caused by de novo missense H4 gene variants. Moreover, it suggests that cases of clinically suspected Angelman syndrome without molecular confirmation should undergo exome or genome sequencing, as novel neurodevelopmental syndromes with phenotypes overlapping with Angelman continue to be discovered.
KW - Angelman syndrome
KW - H4C5
KW - digit anomalies
KW - microcephaly
KW - neurodevelopmental syndrome
KW - tooth anomalies
UR - http://www.scopus.com/inward/record.url?scp=85152458743&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85152458743&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.63193
DO - 10.1002/ajmg.a.63193
M3 - Article
C2 - 36987712
AN - SCOPUS:85152458743
SN - 1552-4825
VL - 191
SP - 1911
EP - 1916
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 7
ER -