H4C5 missense variant leads to a neurodevelopmental phenotype overlapping with Angelman syndrome.
H4C5 missense variant leads to a neurodevelopmental phenotype overlapping with Angelman syndrome.
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H4C5 错义变异导致神经发育表型与天使综合征重叠。
DOI：
10.1002/ajmg.a.63193
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Tekin,Mustafa
中科院分区：
文献类型：
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作者：
Borja,Nicholas;Borjas-Mendoza,Paulo;Bivona,Stephanie;Peart,LéShon;Gonzalez,Joanna;Johnson,BrittneyKeira;Guo,Shengru;Yusupov,Roman;UndiagnosedDiseasesNetwork;Bademci,Guney;Tekin,Mustafa
H4组蛋白基因中的复发性从头错义变体最近与一种新的神经发育综合征相关，该综合征的特征是智力残疾和发育迟缓，以及更多的变量发现，包括身材矮小、小头畸形和面部畸形。一名患有自闭症、发育迟缓、小头畸形和快乐举止的4岁男性通过未诊断疾病网络进行了评估。临床上怀疑他患有Angelman综合征;然而，分子检测呈阴性。基因组测序鉴定了H4组蛋白基因变体H4C5NM_003545.4：c.295T>C，p.Tyr99His，亲本检测证实其为从头产生。该变体符合可能致病分类的标准，是H4 C5中七种已知致病错义变体之一。将我们的先证者的发现与H4相关神经发育综合征的最初描述进行比较，表明他的表型与29名受影响个体中报告的表型非常匹配。因此，这份报告证实了从头错义H4基因变异引起的神经发育综合征的描述。此外，它表明，未经分子确认的临床疑似Angelman综合征病例应进行外显子组或基因组测序，因为与Angelman重叠表型的新型神经发育综合征不断被发现。
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 variantH4C5NM_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 inH4C5. 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.