Abstract：
CHD3 heterozygous variants are associated with Snijders Blok-Campeau syndrome (SBCS) which consists of intellectual disability (ID), macrocephaly, and dysmorphic facies. Most reported variants are missense or loss of function clustered within the ATPase/helicase domain of the protein. We report a severe neurocognitive phenotype caused by biallelic CHD3 variants in two siblings, each inherited from a mildly affected parent. Male and female siblings were referred to the Genetics Clinic due to severe ID and profound dysmorphism. The parents are first cousins of Iranian descent with borderline intellectual abilities. Exome sequencing was performed for the affected female and her parents. A single homozygous candidate variant in the CHD3 gene was detected in the proband: c.5384_5389dup. p.Arg1796_Phe1797insTrpArg, resulting in an in-frame insertion of 2 amino acids located outside the ATPase/helicase domain at the C-terminal region of CHD3-encoding residues. This variant is classified as likely pathogenic according to ACMG guidelines. The variant was detected in a heterozygous state in each parent. Both affected siblings were homozygous, while their unaffected brother did not carry the variant. Biallelic CHD3 variants cause a severe neurodevelopmental syndrome that is distinguishable from SBCS. We assume that the variant type (in-frame insertion) and location may enable CHD3 biallelic variants.
摘要：
CHD3杂合变体与SnijdersBlok-Campeau综合征（SBCS）相关，该综合征由智力障碍（ID）组成，大头畸形,和变形相。大多数报道的变体是错义或功能丧失,聚集在蛋白质的ATP酶/解旋酶结构域内。我们报告了由两个兄弟姐妹的双等位基因CHD3变体引起的严重神经认知表型，每个人都继承自轻度受影响的父母。由于严重的ID和严重的畸形，男性和女性兄弟姐妹被转诊到遗传学诊所。父母是伊朗血统的表亲，具有临界的智力能力。对受影响的女性及其父母进行外显子组测序。在先证中检测到CHD3基因中的单个纯合候选变体:c.5384_5389dup。p.Arg1796_Phe1797insTrpArg,导致位于ATPase/解旋酶结构域之外的CHD3编码残基的C末端区域的2个氨基酸的框内插入。根据ACMG指南，该变体被分类为可能的致病性。在每个亲本中检测到杂合状态的变体。两个受影响的兄弟姐妹都是纯合的，而他们未受影响的兄弟没有携带变种。双等位基因CHD3变体引起可与SBCS区分的严重神经发育综合征。我们假设变体类型(框内插入)和位置可以实现CHD3双等位基因变体。
