Novel PIEZO2 mutation in a new born with congenital arthrogryposis multiplex

Background: A female baby patient, first child of non-consanguineous couple of North-European origin was referred to the Genetics Clinic. During the second and third pregnancy trimester, foetal ultrasound assessment failed to detect any congenital abnormalities. The girl was born at 36 weeks of gestation by caesarean section with birth weight of 2230 grams and head circumference of 34.5 centimetres. She was hospitalized in the neonatal intensive care unit for respiratory support. Clinical assessment detected generalised arthrogryposis with severe bilateral clubfeet deformity, bilateral hip dislocation, clenched hands, ulnar finger deviation, clinodactyly, camptodactyly, and dysmorphic facial features such as brachycephaly, mild hypertelorism, central cleft palate, whistling face, low set, and posteriorly rotated ears. The initial treatment consisted of physiotherapy and casting. She was discharged from the neonatal intensive care unit after 20-days and follow-up was arranged in a specialized care facility.

Methods: Gene panel testing for neuromuscular disorders was performed on Illumina NGS sequencing system and class 4 (likely pathogenic) or 5 (pathogenic) variants were reported and subsequently confirmed by Sanger sequencing.

Results: A de novo heterozygous class 4 variant NM_022068.2(PIEZO2 ): c.8199_8202delAATA p.(Leu2733Phefs*10) in PIEZO2 gene was detected.

Discussion: Congenital arthrogryposis is a broad spectrum of genetic and non-genetic conditions with overlapping clinical features. Heterozygous pathogenic variants in PIEZO2 are known to cause 3 types of arthrogryposis: Gordon syndrome (distal arthrogryposis type 3), Marden-Walker syndrome and Distal arthrogryposis type 5. These clinically and genetically overlapping syndromes are now considered to represent variable expression of the same disorder. Although there is no clear genotype- phenotype correlation, there are some differences among these syndromes. The clinical features of the presented patient tend most to correlate with Gordon syndrome phenotype, which is typically characterized by clenching of hands and feet, camptodactyly, clubfoot, and less frequently, cleft palate. The detected PIEZO2 variant is a frame shift variant, resulting in a premature stop codon. It is located 20 amino acids before the normal stop codon and has not been previously reported. This PIEZO2 gene variant was presumed to be likely pathogenic given that there is another reported patient with proven pathogenic PIEZO2 gene variant that is located downstream of this PIEZO2 position.

Conclusion: A patient with phenotype of Gordon syndrome is presented, one of the three disorders known to be caused by PIEZO2 pathogenic variants.