Novel Insights From In Silico Analysis of Biallelic ALPL (c.1001G/A and c.571G/A) in Two Mennonite Families Leading to Hypophosphatasia

This report aimed to describe two families of Mennonite heritage affected with hypophosphatasia (HPP) and biallelic <i>ALPL</i> c.1001G>A/c.571G>A in four individuals. Additionally, we conduct a systematic review of studies considering the above compound heterozygous genotype and present novel insights and evidence inferred from in silico predictions using Ensembl's Variant Effect Predictor (VEP) platform and STRING protein-protein interaction (PPI) network analysis to explore these genetic variations and plausible interacting pathways for the disorder that remain for consideration in future studies. Intrafamilial and interfamilial variability of phenotypes was observed in the four patients affected with the identical <i>ALPL</i> c.1001G>A/c.571G>A mutation. In contrast, in the seven unaffected family members, a specific genotype was not available. Seven eligible studies exploring <i>ALPL</i> c.1001G>A/c.571G>A were identified, and significant heterogeneity (<i>P</i> < 0.05) was observed across four studies. Ensembl VEP inferred a dual effect for rs121918007 and rs121918009, involving 17 variants located in the exome and four classified as non-coding associated with all HPP presentations, as well as serum alkaline phosphatase levels, choline phosphate levels, osteogenesis imperfecta, and inborn genetic diseases. PPI network modeling predicted 10 genes (<i>PTS, NBPF3, SLC30A7, TPK1, NTPCR, BGLAP, RUNX2, ENPP1, SLC30A6, GCH1</i>) interacting with <i>ALPL</i>, highlighting their potential impact on bone formation and homeostasis, metabolism, and gene expression. These results may shed light on HPP variability by disrupting key metabolic and transcriptional pathways and provide a comprehensive view of their functional relevance, which suggests a complex genetic etiology for HPP.