Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran.
Department of Radiology, Mahdieh Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Clin Genet. 2020 Jun;97(6):915-919. doi: 10.1111/cge.13730. Epub 2020 Mar 10.
Variants in transcriptional activator Gli Kruppel Family Member 3 (GLI3) have been reported to be associated with several phenotypes including Greig cephalopolysyndactyly syndrome (MIM #175700), Pallister-Hall syndrome (PHS) (MIM #146510), postaxial polydactyly types A1 (PAPA1) and B (PAPB) (MIM #174200), and preaxial polydactyly type 4 (MIM #174700). All these disorders follow an autosomal dominant pattern of inheritance. Hypothalamic hamartomas (MIM 241800) is associated with somatic variants in GLI3. We report a related couple with parents having PAPA1 and PAPB, who had a fetus with a phenotype most compatible with PHS. Molecular analyses demonstrated homozygosity for a pathogenic GLI3 variant (c.1927C > T; p. Arg643*) in the fetus and heterozygosity in the parents. The genetic analysis in this family demonstrates that heterozygosity and homozygosity for the same GLI3 variant can cause a different phenotype. Furthermore, the occurrence of Pallister-Hall-like syndrome in a homozygous patient should be taken into account in genetic counseling of families with PAPA1/PAPB.
转录激活因子Gli Kruppel 家族成员 3（GLI3）的变异已被报道与多种表型相关，包括 Greig 头面多并指综合征（MIM #175700）、帕利斯特-霍尔综合征（PHS）（MIM #146510）、后轴多指畸形 A1 型（PAPA1）和 B 型（PAPB）（MIM #174200）以及前轴多指畸形 4 型（MIM #174700）。所有这些疾病均遵循常染色体显性遗传模式。下丘脑错构瘤（MIM 241800）与 GLI3 的体细胞变异相关。我们报告了一对相关的父母，他们患有 PAPA1 和 PAPB，其胎儿的表型与 PHS 最相符。分子分析显示，胎儿存在 GLI3 致病性变异（c.1927C>T;p.Arg643*）的纯合性，而父母则为杂合性。该家系的遗传学分析表明，同一 GLI3 变异的杂合性和纯合性可导致不同的表型。此外，在 PAPA1/PAPB 家族的遗传咨询中，应考虑 Pallister-Hall 样综合征在纯合患者中的发生。
