We report the case of a PMM2-CDG French child of Caucasian descent. She was born at term with a length of 48 cm for 3.110 kg, after uncomplicated pregnancy with vaginal delivery. The AGPAR score was 10 both at 1 minute and 5 minutes and the newborn screening results were normal. The parents are unrelated and the 6-years older brother is healthy. Parents reported abnormal abrupt movements of the child after birth that stopped spontaneously.
Biologically, elevated transaminases TGO = 50 UI/ L, TGP = 51 [normal values 10-35 UI/L] and abnormal coagulation parameters with ATIIIA = 63% [normal values 80-120%] and FXI 53% at the lower limit [normal values 50-150%] were assayed. The cytology and the thyroid function were normal.
The clinical examination at 9 months of age revealed ataxia, hypotonia, hyperlaxity, strabismus, esotropia, feeding difficulties, and inverted nipples. The child was calm and exclusively breastfed with an absence of facial dysmorphia and no sleeping disorders. At that time, the girl presented an inability to reach a seated posture. The diagnosis of CDG was oriented by an abnormal pattern in serum transferrin isoelectrofocusing (8) with an elevation of asialo- and disialo-transferrin, typical from a type I CDG (Fig. 1). Brain MRI revealed cerebellar abnormalities with vermis hypoplasia. The child finally reaches a seated posture at 11 months of age.
Direct Sanger sequencing of the 8 exons of PMM2 reported a seemingly homozygous variant rs200203569 NM_000303.3(PMM2): c.323C>T in exon 4. The variant leads to a missense substitution of alanine 108 to proline (p.Ala108Pro), commonly named A108V, that is known to be pathogenic (ClinVar, SIFT, Mutation Taster). The A108V mutation is quite rare and is often associated with R141H, the most common deleterious PMM2 mutation, in compound heterozygous patients (9). A homozygous presentation of R141H variant is thought to be incompatible with life as no case was reported so far (10). For the A108V variant, the gnomAD (2.1) website reports a frequency of 0.0012% in the overall population. To our knowledge, no homozygous A108V patients are reported in the literature and, as the parents were unrelated, further genetic explorations were conducted. Direct Sanger sequencing of PMM2 of the paternal DNA reported a heterozygous A108V mutation while no mutation was found in the mother. A quantitative PCR (qPCR) of the 13 exons was performed, showing a reduction of the DNA of the gene by 50% in the mother and the proband from exon 3 to exon 8, the last exon of PMM2 (Fig. 2). A heterozygous deletion of PMM2 gene was then suspected. To evaluate the extent of the deletion that goes beyond PMM2 gene, Whole Genome Sequencing (WGS) was performed. WGS was preferred to CGH array to accurately determine the exact position of the breakpoints. WGS allowed to delineate the deletion of 70453 bp in position chr16:8,897,826-8,968,278 (Fig. 3). In the HGMD database, the largest deletion reported is 28 kb-long.
The deletion also affects a part of CARHSP1 (Calcium Regulated Hear Stable Protein 1) (OMIM: 616885) gene that plays a role in TNF mRNA stabilization, seemingly not affecting the phenotype.