TY - JOUR
T1 - Human phenotype caused by biallelic KDM4B frameshift variant
AU - Takada, Sanami
AU - Silva, Sebastián
AU - Zamorano, Ivonne
AU - Pérez, Andrea
AU - Iwabuchi, Chisato
AU - Miyake, Noriko
N1 - Publisher Copyright:
© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
PY - 2024/1
Y1 - 2024/1
N2 - KDM4B (MIM*609765, NM_015015.3, formerly JMJD2B) encodes a histone demethylase and regulates gene expression via demethylation, mainly of H3K9 tri-methylation. Heterozygous KDM4B loss-of-function variants cause autosomal dominant intellectual developmental disorder 65 (MIM#619320), which is characterized by global developmental delay, intellectual disability, language and gross motor delays, structural brain anomalies, characteristic facial features, and clinodactyly. Although the majority of reported patients have de novo pathogenic variants, some patients inherit pathogenic variants from affected parents. To our knowledge, only 23 patients with heterozygous KDM4B variants have been reported to date, and there are no reports of patients with biallelic KDM4B pathogenic variants. Herein, we report a female patient with a biallelic KDM4B frameshift variant (NM_015015.3: c.1384_1394delinsGGG, p.(Leu462Glyfs*43)) located at exon 12 of 23 protein-coding exons, which is thought to be subject to nonsense-mediated mRNA decay and no protein production. She presented developmental and language delays and a hypotonic and characteristic face. The patient's phenotype was more obvious than that of her mother, who is heterozygous for the same variant. Although declining birth rate (embryonic lethality in male mice) in homozygous knockout mice has been demonstrated, our report suggests that homozygous KDM4B frameshift variants can be viable in humans at least female.
AB - KDM4B (MIM*609765, NM_015015.3, formerly JMJD2B) encodes a histone demethylase and regulates gene expression via demethylation, mainly of H3K9 tri-methylation. Heterozygous KDM4B loss-of-function variants cause autosomal dominant intellectual developmental disorder 65 (MIM#619320), which is characterized by global developmental delay, intellectual disability, language and gross motor delays, structural brain anomalies, characteristic facial features, and clinodactyly. Although the majority of reported patients have de novo pathogenic variants, some patients inherit pathogenic variants from affected parents. To our knowledge, only 23 patients with heterozygous KDM4B variants have been reported to date, and there are no reports of patients with biallelic KDM4B pathogenic variants. Herein, we report a female patient with a biallelic KDM4B frameshift variant (NM_015015.3: c.1384_1394delinsGGG, p.(Leu462Glyfs*43)) located at exon 12 of 23 protein-coding exons, which is thought to be subject to nonsense-mediated mRNA decay and no protein production. She presented developmental and language delays and a hypotonic and characteristic face. The patient's phenotype was more obvious than that of her mother, who is heterozygous for the same variant. Although declining birth rate (embryonic lethality in male mice) in homozygous knockout mice has been demonstrated, our report suggests that homozygous KDM4B frameshift variants can be viable in humans at least female.
KW - autosomal dominant intellectual developmental disorder 65
KW - autosomal recessive inheritance
KW - exome sequencing
KW - KDM4B
UR - http://www.scopus.com/inward/record.url?scp=85166535568&partnerID=8YFLogxK
U2 - 10.1111/cge.14409
DO - 10.1111/cge.14409
M3 - Article
C2 - 37526414
AN - SCOPUS:85166535568
SN - 0009-9163
VL - 105
SP - 72
EP - 76
JO - Clinical Genetics
JF - Clinical Genetics
IS - 1
ER -