Novel ALPL Splice-Site Mutation Identified as Cause of Severe Perinatal Hypophosphatasia

Researchers have identified a previously unreported genetic mutation as the cause of severe perinatal hypophosphatasia in an aborted fetus from a consanguineous Iranian family, according to a study published in BMC Medical Genomics. The finding concerns hypophosphatasia, a rare inherited condition of bone and mineral metabolism caused by mutations in the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase, an enzyme essential for proper bone mineralization.

The investigation began with an aborted fetus that had shown severe skeletal abnormalities. The family, in which the parents are consanguineous, had a documented history of similar adverse pregnancy outcomes, prompting the research team to search for an underlying genetic explanation rather than treating the loss as an unexplained recurrence.

To pinpoint the cause, the team performed whole exome sequencing on genomic DNA extracted from the aborted fetus’s tissue.

The sequencing revealed a novel homozygous variant in the ALPL gene, designated NM_000478.6:c.863–2 A > G, meaning both copies of the gene carried the mutation. Sanger sequencing confirmed the homozygous state in the fetus and showed that both consanguineous parents were heterozygous carriers, each holding one mutated and one unaltered copy.

The variant’s position is critical: it sits at the canonical acceptor splice site of intron 8.

The researchers deployed a comprehensive suite of computational prediction tools, categorized into three groups: splicing impact prediction using SpliceAI and Human Splicing Finder, general deleteriousness assessment using DANN and GenoCanyon, and evolutionary conservation analysis using PhyloP and PhastCons.

Several lines of evidence supported the variant’s pathogenic classification. It was absent from major population databases, including gnomAD and the Iranome database, indicating it is not a common benign variation in the general population or in Iranian-specific reference data.

Hypophosphatasia has a highly variable clinical spectrum, with infantile forms often being severe or lethal, according to the study. The authors state that the homozygous splice-site mutation is the definitive cause of severe perinatal hypophosphatasia in this family, and that the finding expands the known mutational spectrum of ALPL while underscoring the importance of this specific splice site for correct synthesis of the enzyme.

Beyond its diagnostic significance for this single case, the identification carries practical consequences for the family’s future. The authors note that knowing the specific variant facilitates accurate genetic counseling and prenatal diagnosis for future pregnancies in this family. The study was published as open access research on 23 October 2026, and the version shared at publication is a peer-reviewed, accepted manuscript that remains citable with a permanent DOI while awaiting its final version of record.

Subject of Research: A novel homozygous ALPL splice-site mutation identified as the genetic cause of severe perinatal hypophosphatasia in a consanguineous Iranian family

Article Title: A novel homozygous splice-site mutation in ALPL (c.863–2 A > G) causes severe perinatal hypophosphatasia in an Iranian family

Article References: shams, L., Karimimanesh, M., zahraei, M. S., Yavari, M., Dizaji, B. F., Homai, F. Z., Rezaie, N., & Pourghadamyari, H. (2026). A novel homozygous splice-site mutation in ALPL (c.863–2 A > G) causes severe perinatal hypophosphatasia in an Iranian family. BMC Medical Genomics. https://doi.org/10.1186/s12920-026-02498-0

Image Credits: AI Generated

DOI: 10.1186/s12920-026-02498-0

Keywords: hypophosphatasia, ALPL, splice-site mutation, whole exome sequencing, genetics, consanguinity, perinatal lethal, Sanger sequencing, in silico prediction, ACMG classification, Iranian family, prenatal diagnosis