A Case of PMM2-CDG Caused by an A108V Mutation Associated With a Heterozygous 70 Kilobases Deletion

Background: Congenital Disorders of Glycosylation (CDG) are a large group of inherited inborn errors of metabolism with more than 140 different CDG types reported to date (1). The first characterized is also the most common, PMM2-CDG, with an autosomal recessive transmission. The PMM2 gene is encoding a phosphomannomutase. Case report: We report the case of a French child, from healthy and unrelated parents, presenting congenital ataxia with hypotonia, hyperlaxity, inverted nipples and alteration of the liver function and coagulation parameters. Transferrin isoelectrofocusing revealed a typical type I CDG profile. Direct Sanger sequencing and quantitative PCR of PMM2 revealed a unique and novel genotype. On one allele, the patient was heterozygote with a known missense variant rs200203569 NM_000303.3(PMM2):c.323C>T, p.Ala108Val in exon 4. On the second allele, WGS confirmed the presence of a novel heterozygous 70453 bp deletion encompassing 6 exons of PMM2 at position chr16:8,897,826-8,968,278. Conclusion: As the maximum length of a PMM2 deletion reported by HGMS database is 28 kb, we identified the largest heterozygous deletion reported so far. The observation reveals the impact of a thorough diagnostic testing on genetic counselling: hasty conclusion of homozygosity in the case of a relatively rare variant found in an index patient with unrelated parents can be avoided using whole genome sequencing.