FRI0015 EXON 5 DUPLICATION IN ALPL GENE AS THE GENETIC CAUSE OF HYPOPHOSPATASIA IN A 3 YEAR OLD GIRL

Background: Hypophosphatasia (HPP) (OMIM 146300, 241510, 241500) is an inborn error of metabolism caused by pathogenic variants in the gene ALPL that codifies for the tissue non-specific alkaline phosphastase (1). The disease presents with different degrees of severity, from perinatal forms to mild adult phenotypes, including odontohypophosphatasia where only dental complications are described. Until now, more than 380 variants are described to cause HPP, and only 2,9% are large deletions or duplications (http://www.sesep.uvsq.fr/03_hypo_mutations.php). Objectives: Identify the genetic cause of the disease in the girl with an infantile HPP. Methods: The patient is a female child born by cesarean at week 37 of gestation. The child required reanimation. Weight, length and cranial perimeter were bellow percentile 10th (1735g, 42 cm, 31,5 cm respectively). She presented and obstetric femur fracture and normal to low alkaline phosphatase (AF) activity (158 UI/L (reference 142-335 UI/L). After fracture, a second determination of AF (127UI/L) and pyridoxal-5′-phosphate (PLP) concentration (240,41 mgc/L, reference 6,4-23) were measured. Skeletal interrogation revealed low bone mineralization, tongues of radiofluency in long bones and narrow ribs. A clinical diagnose of hypophospatasia was done. At the three year-old revision she still presents weight and length below percentile 15th, a mild cardiac problem but had no fractures since birth. She presents lung malformation, and cannot eat solid food. She still has low AF activity (154 U/L) and high PLP (69,13 μg/L; refences 150-350 U/L and 3,6-18 μg/L respectively). She is on school but has language delay. Genetic analysis: DNA was extracted from peripheral blood of patient and her mother. From patient’s sample we perfomed Sanger sequencing of exons 1 to 12, CGH analysis using a customized whole genome CGH 4x44k Agilent array enriched in probes for ALPL gene (130 probes) and qPCR of exons 2 to 12. Results: The study of copy number variants of ALPL gene by qPCR revealed a duplication in exon 5 in the patient and her mother. Conclusion: Although gross deletions and duplications are a rare phenomenon in HPP, here we present a case of a 3 year old child and her mother that present a single exon duplication as a probable cause of the disease. Actually, the mother is under clinical evaluation. Part of the active site is codified in exon 5, suggesting that a duplication might alter the correct structure and/or function of the protein. So, including the screening of copy number variants during the genetic screening is important to reach the correct diagnosis of HPP. References: [1] Whyte, M.P. (2017). Hypophosphatasia: An overview For 2017. Bone 102, 15–25. Disclosure of Interests: Eva Gonzalez-Roca Paid instructor for: Alexion, Manuela Munoz-Torres: None declared, Pilar Carrasco: None declared, Antonio Gonzalez-Meneses: None declared, Raquel Yahyaoui: None declared, Ricard Isanta: None declared, Etienne Mornet: None declared