Neonatal rhizomelic chondrodysplasia punctata type 2 caused by a novel homozygous variant in the GNPAT gene.

Upper limbs radiographs show rhizomelic shortening of both humeri, flared metaphyses, and stippled calcifications of proximal and distal epiphyses.

Sayed J, Gamal A, Theyab A, Algahtani M, and Aldaadi BB. (2023) Neonatal rhizomelic chondrodysplasia punctata type 2 caused by a novel homozygous variant in the GNPAT gene. Clinical Case Reports

Rhizomelic chondrodysplasia punctata (RCDP) is a rare genetic disease caused by an inability to produce plasmalogens. Plasmalogens are a special class of phospholipid that contain a vinyl-ether bond at the sn-1 position. Plasmalogens have important roles in cell membrane structure and fluidity, vesicular fusion, are a major component of myelin, and have antioxidative properties. There are five crucial genes in plasmalogen biosynthesis and the mutation of any one results in an inability to synthesize plasmalogens. One of these genes is glyceronephosphate O-acyltransferase (GNPAT) gene which encodes the first enzyme in the biosynthetic pathway and is responsible for RCDP type 2. RCDP is characterized by shortened proximal limbs, congenital cataracts, punctate calcifications, seizures, chronic respiratory illness, and developmental delays. Here, Sayed et al are describing a novel case of a splicing homozygous variant in GNPAT in an infant in Saudi Arabia.

The male subject was born at 36 weeks with respiratory distress, dysmorphic facial appearance, and short limbs. At 35 weeks gestation ultrasonography demonstrated that the subject’s fetal growth was below the fifth percentile and all short and long bones were below reference percentiles for the gestational age. The weight at birth was 2205g, which is below the 25th percentile for gestational age. He had proximal shortening of upper and lower limbs, as well as depressed nasal bridge, broad nose, coarse facial features, long philtrum, and contractures at thigh, knee, shoulder, elbow, wrist, and fingers. The subject also had bilateral polar cataracts and evidence of restrictive lung disease.

To confirm the diagnosis, whole exome sequencing was performed. A novel splicing homozygous variant in GNPAT was discovered: GNPAT (NM_014236.4):c.1602+1G>A (p.?), Chr1 (GRCh37):g.231408138G>A. At the time of publication, this variant had not been reported nor had been found in the general population databases. This change in the sequence of intron 11 positions affects a donor splice site, the 5’ end of the intron. Developed algorithms predict that this change in sequence could result in disruption of the splice site, but this has not been confirmed by transcriptional studies yet. The mutation variant described is designated as potentially pathogenic based on this sequencing information and the American College of Medical Genetics (ACMG) guidelines for RCDP Type 2 that are consistent with the phenotype seen in this subject. In addition, since this GNPAT gene variant was homozygous, a genetic diagnosis was confirmed.

Sayed et al have described a GNPAT gene variant that has not previously been reported or found in the general population databases. He had a classic presentation of RCDP with dysmorphic facial features, shortened proximal limbs, punctate calcifications, contractures, and polar cataracts. Exome sequencing confirmed the exact change in the gene sequence of intron 11 resulting in this variation. Although the family of the subject were not willing to do further testing to confirm the GNPAT protein structure due to this mutation, because of the phenotype present in the subject, the diagnosis was able to be confirmed. The final update for the subject was that he is 4 months old and weighs 3 450g, is growing slowly and has difficulty gaining weight, feeds through a nasogastric tube, and has oxygen support of 28% by nasal cannula. RCDP is a disease with very severe pathology, however, it is ultra-rare and is not commonly known. More awareness for this disease will allow for more research and for faster diagnoses.