PIGH deficiency can be associated with severe neurodevelopmental and skeletal manifestations,Clinical Genetics

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PIGH deficiency can be associated with severe neurodevelopmental and skeletal manifestations
Clinical Genetics ( IF 2.9 ) Pub Date : 2020-11-06 , DOI: 10.1111/cge.13877
Camille Tremblay-Laganière ₁ , Rauan Kaiyrzhanov ₂ , Reza Maroofian ₂ , Thi Tuyet Mai Nguyen ₁ , Kamran Salayev ₃ , Ilana T Chilton ₄ , Wendy K Chung _{4,

5} , Jill A Madden ₆ , Chanika Phornphutkul ₇ , Pankaj B Agrawal _{6,

8} , Henry Houlden ₂ , Philippe M Campeau ₁

Affiliation

Phosphatidylinositol Glycan Anchor Biosynthesis class H (PIGH) is an essential player in the glycosylphosphatidylinositol (GPI) synthesis, an anchor for numerous cell membrane‐bound proteins. PIGH deficiency is a newly described and rare disorder associated with developmental delay, seizures and behavioral difficulties. Herein, we report three new unrelated families with two different bi‐allelic PIGH variants, including one new variant p.(Arg163Trp) which seems associated with a more severe phenotype. The common clinical features in all affected individuals are developmental delay/intellectual disability and hypotonia. Variable clinical features include seizures, autism spectrum disorder, apraxia, severe language delay, dysarthria, feeding difficulties, facial dysmorphisms, microcephaly, strabismus, and musculoskeletal anomalies. The two siblings homozygous for the p.(Arg163Trp) variant have severe symptoms including profound psychomotor retardation, intractable seizures, multiple bone fractures, scoliosis, loss of independent ambulation, and delayed myelination on brain MRI. Serum iron levels were significantly elevated in one individual. All tested individuals with PIGH deficiency had normal alkaline phosphatase and CD16, a GPI‐anchored protein (GPI‐AP), was found to be decreased by 60% on granulocytes from one individual. This study expands the PIGH deficiency phenotype range toward the severe end of the spectrum with the identification of a novel pathogenic variant.

中文翻译：

PIGH缺乏可能与严重的神经发育和骨骼表现有关

磷脂酰肌醇聚糖锚定生物合成 H 类 (PIGH) 是糖基磷脂酰肌醇 (GPI) 合成的重要参与者，它是许多细胞膜结合蛋白的锚。PIGH 缺乏症是一种新描述的罕见疾病，与发育迟缓、癫痫发作和行为困难有关。在这里，我们报告了三个新的无关家族，它们具有两个不同的双等位基因PIGH变体，包括一个新的变体 p.(Arg163Trp)，它似乎与更严重的表型有关。所有受影响个体的共同临床特征是发育迟缓/智力残疾和肌张力减退。不同的临床特征包括癫痫发作、自闭症谱系障碍、失用症、严重的语言延迟、构音障碍、喂养困难、面部畸形、小头畸形、斜视和肌肉骨骼异常。p.(Arg163Trp) 变体纯合子的两个兄弟姐妹有严重的症状，包括严重的精神运动迟缓、顽固性癫痫发作、多处骨折、脊柱侧弯、丧失独立行走能力和脑 MRI 上的髓鞘形成延迟。一名个体的血清铁水平显着升高。所有 PIGH 缺乏的测试个体的碱性磷酸酶和 CD16 均正常，发现一个 GPI 锚定蛋白 (GPI-AP) 在一个个体的粒细胞上减少了 60%。本研究通过鉴定一种新的致病性变异，将 PIGH 缺乏表型范围扩大到严重的范围。

更新日期：2021-01-14

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