Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut, Lebanon.
School of Medicine, Lebanese American University, Beirut, Lebanon.
Diagn Pathol. 2019 Nov 4;14(1):123. doi: 10.1186/s13000-019-0902-5.
Hyperphosphatasia with mental retardation syndrome (HPMRS) is a recessive disorder characterized by high blood levels of alkaline phosphatase together with typical dysmorphic signs such as cleft palate, intellectual disability, cardiac abnormalities, and developmental delay. Genes involved in the glycosylphosphatidylinositol pathway and known to be mutated in HPMRS have never been characterized in the Lebanese population.
Herein, we describe a pair of monozygotic twins presenting with severe intellectual disability, distinct facial dysmorphism, developmental delay, and increased alkaline phosphatase level. Two individuals underwent whole exome sequencing followed by Sanger sequencing to confirm the co-segregation of the mutation in the consanguineous family. A biallelic loss of function mutation in PGAP3 was detected. Both patients were homozygous for the c.203delC (p.C68LfsX88) mutation and the parents were carriers confirming the founder effect of the mutation. High ALP serum levels confirmed the molecular diagnosis.
Our findings have illustrated the genomic profile of PGAP3-related HPMRS which is essential for targeted molecular and genetic testing. Moreover, we found previously unreported clinical findings such as hypodontia and skin hyperpigmentation. These features, together with the novel mutation expand the phenotypic and genotypic spectrum of this rare recessive disorder.
高磷酸酶血症伴智力迟钝综合征（HPMRS）是一种常染色体隐性疾病，其特征是血液碱性磷酸酶水平升高，同时伴有典型的发育异常体征，如腭裂、智力障碍、心脏异常和发育迟缓。涉及糖基磷脂酰肌醇途径的基因，已知在 HPMRS 中发生突变，但从未在黎巴嫩人群中进行过特征描述。
在此，我们描述了一对表现出严重智力障碍、明显面部发育异常、发育迟缓及碱性磷酸酶水平升高的同卵双胞胎。对这两个人进行了外显子组测序，然后进行 Sanger 测序，以确认突变在近亲家庭中的共分离。在 PGAP3 中检测到双等位基因失活突变。两位患者均为 c.203delC（p.C68LfsX88）突变的纯合子，而父母为携带者，证实了该突变的创始人效应。高 ALP 血清水平证实了分子诊断。
我们的研究结果阐明了 PGAP3 相关 HPMRS 的基因组特征，这对于靶向分子和基因测试至关重要。此外，我们发现了以前未报道过的临床发现，如牙缺失和皮肤色素沉着过度。这些特征，连同新的突变，扩大了这种罕见隐性疾病的表型和基因型谱。
