Corporate Medical & Clinical Affairs, Abu Dhabi Health Services Company - SEHA, United Arab Emirates; Department of Molecular Genetics, University of Toronto, Toronto, Canada.
Academic Affairs Department, Corniche Hospital, Abu Dhabi Health Services Company - SEHA, United Arab Emirates.
Eur J Med Genet. 2022 May;65(5):104501. doi: 10.1016/j.ejmg.2022.104501. Epub 2022 Apr 1.
We report on three male siblings who presented prenatally with a nearly identical combination of congenital anomalies and who died shortly after preterm birth. The first baby was a singleton pregnancy, and the other two babies were dichorionic diamniotic twins. Key features included: left-sided congenital diaphragmatic hernia, inferior vermian dysgenesis/hypoplasia, prenasal edema, cleft palate, micropenis/ambiguous genitalia (in 2 of 3 babies), bilateral renal pelvic dilatation (in twins, first baby showed slightly enlarged kidneys) and polyhydramnios (in 2 of 3). Whole genome sequencing performed on DNA from all three babies revealed homozygous missense PIGL gene variants: c.438C>A, p.(Phe146Leu). Both parents were heterozygous carriers of the variant. The reporting clinical laboratory classified the change as a variant of uncertain significance (VUS), and concluded "A genetic diagnosis of autosomal recessive CHIME syndrome is possible". The PIGL gene has been reported to cause two different autosomal recessive conditions: CHIME syndrome and Mabry syndrome. CHIME (Zunich neuroectodermal syndrome) is characterized by ocular Colobomas, Heart defects, Ichthyosiform dermatosis, Mental retardation (intellectual disability), and Ear anomalies, including conductive hearing loss. Mabry [aka hyperphosphatasia mental retardation syndrome (HPMRS)] is characterized by severe developmental delay, moderate to severe intellectual disability, distinctive facial features, brachytelephalangy, increased serum levels of alkaline phosphatase (ALP), and recurrent seizures. Neonatal demise and lack of postmortem examination precluded assessment of some key features (including seizures, developmental delay, ALP levels, colobomas and deafness), but overlapping features observed included cleft palate, brain anomalies, genitourinary abnormalities and prenasal edema. Notably, diaphragmatic hernia is not a common feature of either condition, but is a cardinal feature of Fryns syndrome. The genetic etiology of Fryns syndrome has not been definitively established, although, much like CHIME and Mabry syndrome, can be caused by variants in glycosylphosphatidylinositol (GPI) anchor pathway genes. Our findings suggest further overlap between inherited GPI deficiencies, and possible expansion of the clinical phenotype of PIGL-related disorders to include prenatal presentations with congenital diaphragmatic hernia. Although reported as a VUS, we present phenotypic and familial segregation evidence that supports likely pathogenicity of the c.438C>A variant.
我们报告了三例男性同胞，他们在产前表现出几乎相同的先天性异常组合，并在早产不久后死亡。第一个婴儿是单胎妊娠，而另外两个婴儿是双绒毛膜双羊膜双胞胎。主要特征包括：左侧先天性膈疝、下蚓部发育不良/发育不全、鼻前水肿、腭裂、小阴茎/生殖器模糊（3 例中有 2 例）、双侧肾盂扩张（双胞胎中，第一个婴儿的肾脏稍大）和羊水过多（3 例中有 2 例）。对所有三个婴儿的 DNA 进行全基因组测序显示，纯合错义 PIGL 基因突变：c.438C>A，p.(Phe146Leu)。父母双方均为该变异的杂合携带者。报告的临床实验室将该变化归类为意义不明的变异（VUS），并得出“可能存在常染色体隐性 CHIME 综合征的遗传诊断”的结论。PIGL 基因已被报道引起两种不同的常染色体隐性疾病：CHIME 综合征和 Mabry 综合征。CHIME（Zunich 神经外胚层综合征）的特征是眼部 Colobomas、心脏缺陷、鱼鳞样皮肤病、智力迟钝（智力障碍）和耳部异常，包括传导性听力损失。Mabry [又名高磷酸酶智力迟钝综合征（HPMRS）]的特征是严重发育迟缓、中度至重度智力障碍、独特的面部特征、短指（趾）、碱性磷酸酶（ALP）血清水平升高、反复癫痫发作。新生儿死亡和缺乏尸检排除了一些关键特征（包括癫痫发作、发育迟缓、ALP 水平、Colobomas 和耳聋）的评估，但观察到的重叠特征包括腭裂、脑异常、泌尿生殖系统异常和鼻前水肿。值得注意的是，膈疝不是任何一种疾病的常见特征，但却是 Fryns 综合征的一个主要特征。Fryns 综合征的遗传病因尚未明确确定，尽管与 CHIME 和 Mabry 综合征一样，它可能是由糖基磷脂酰肌醇（GPI）锚定途径基因的变异引起的。我们的研究结果表明，遗传性 GPI 缺乏症之间存在进一步的重叠，并且 PIGL 相关疾病的临床表型可能扩展到包括产前出现先天性膈疝。尽管被报告为 VUS，但我们提供了表型和家族分离证据，支持 c.438C>A 变异的可能致病性。
