[Mutation analysis for two hypophosphatasia families with targeted next-generation sequencing]

Area of Science:

• Genetics
• Molecular Biology
• Pediatrics

Background:

• Perinatal hypophosphatasia (HPP) is a severe genetic disorder.
• Alkaline phosphatase (ALPL) gene mutations are the primary cause of HPP.
• Understanding the genetic basis of HPP is crucial for diagnosis and management.

Purpose of the Study:

• To identify mutations in the ALPL gene in two Chinese families affected by perinatal HPP.
• To elucidate the genetic mechanism underlying HPP in these families.
• To evaluate the utility of Next-Generation Sequencing (NGS) and Sanger sequencing for HPP diagnosis.

Main Methods:

• Exome sequencing using an osteology system panel via NGS was performed on mothers of HPP fetuses.
• Polymerase chain reaction (PCR) and Sanger sequencing were used for validation in family members and 200 healthy controls.
• Autosomal recessive inheritance patterns were analyzed.

Main Results:

• Family 1: Compound heterozygous ALPL mutations (c.333delC and c.568_570delAAC) identified in the affected fetus.
• Family 2: Compound heterozygous ALPL mutations (c.1250A>G and c.1166C>A) identified in the affected fetus.
• A novel mutation, ALPL gene c.333delC (p.Gly112AlafsX10), was discovered and not present in healthy controls.

Conclusions:

• Identified ALPL gene mutations are strongly associated with perinatal HPP in the studied families.
• NGS combined with Sanger sequencing offers an accurate and efficient approach for diagnosing HPP.
• This study contributes to understanding the genetic heterogeneity of HPP.