TY - JOUR
T1 - Biallelic loss of OTUD7A causes severe muscular hypotonia, intellectual disability, and seizures
AU - Suzuki, Hisato
AU - Inaba, Mie
AU - Yamada, Mamiko
AU - Uehara, Tomoko
AU - Takenouchi, Toshiki
AU - Mizuno, Seiji
AU - Kosaki, Kenjiro
AU - Doi, Motomichi
N1 - Publisher Copyright:
© 2020 Wiley Periodicals LLC
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020
Y1 - 2020
N2 - The heterozygous deletion of 15q13.3 is a recurrently observed microdeletion syndrome associated with a relatively mild phenotype including learning disability and language impairment. In contrast, the homozygous deletion of 15q13.3 is extremely rare and is associated with a much severer phenotype that includes epileptic encephalopathy, profound intellectual disability, and hypotonia. Which of the genes within the deleted interval is responsible for the more severe features when biallelically deleted is currently unknown. Here, we report a patient with profound hypotonia, severe intellectual disability, and seizures who had biallelic loss-of-function variants in OTUD7A: a 15q13.3 deletion including the OTUD7A locus, and a frameshift OTUD7A variant c.1125del, p.(Glu375Aspfs*11). Unexpectedly, both aberrations occurred de novo. Our experiment using Caenorhabditis elegans showed that worms carrying a corresponding homozygous variant in the homolog OTUB-2 exhibited weakened muscle contraction suggestive of aberrant neuromuscular transmission. We concluded that the biallelic complete loss of OTUD7A in humans represents a presumably new autosomal recessive disorder characterized by profound hypotonia, severe intellectual disability, and seizures.
AB - The heterozygous deletion of 15q13.3 is a recurrently observed microdeletion syndrome associated with a relatively mild phenotype including learning disability and language impairment. In contrast, the homozygous deletion of 15q13.3 is extremely rare and is associated with a much severer phenotype that includes epileptic encephalopathy, profound intellectual disability, and hypotonia. Which of the genes within the deleted interval is responsible for the more severe features when biallelically deleted is currently unknown. Here, we report a patient with profound hypotonia, severe intellectual disability, and seizures who had biallelic loss-of-function variants in OTUD7A: a 15q13.3 deletion including the OTUD7A locus, and a frameshift OTUD7A variant c.1125del, p.(Glu375Aspfs*11). Unexpectedly, both aberrations occurred de novo. Our experiment using Caenorhabditis elegans showed that worms carrying a corresponding homozygous variant in the homolog OTUB-2 exhibited weakened muscle contraction suggestive of aberrant neuromuscular transmission. We concluded that the biallelic complete loss of OTUD7A in humans represents a presumably new autosomal recessive disorder characterized by profound hypotonia, severe intellectual disability, and seizures.
KW - 15q13.3 microdeletion syndrome
KW - CHRNA7
KW - OTUD7A
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U2 - 10.1002/ajmg.a.62054
DO - 10.1002/ajmg.a.62054
M3 - Article
AN - SCOPUS:85098326742
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
SN - 1552-4825
ER -