A Rare Arthrogryposis Syndrome with Multiple Anomalies Diagnosed by Whole Exome Sequencing

Abstract

A 31-year-old gravida 1 para 0 was referred to our institution following a fetal anatomic survey demonstrating clubbed feet, flexed wrists, and skin edema. Ultrasound evaluation demonstrated these findings in addition to hemivertebrae, short long bones, contractures of the elbows, wrists, knees, and ankles with limited movement at the shoulders and hips. Further, macrocephaly, microphthalmia, low set ears, micrognathia, hepatomegaly, and an omphalocele were noted. Following termination of the pregnancy, whole exome sequencing ultimately identified compound heterozygous mutations in the NEK9 gene. One mutation in our case, c.136G>T, has never been reported; the other, c.1432del, has been reported once. To date, NEK9 mutations have been documented in three families with all affected individuals diagnosed with arthrogryposis. Our patient underwent targeted gene variant testing in two subsequent pregnancies, confirming identification of one of the two familial NEK9 gene mutations each time. Both pregnancies culminated in term deliveries of healthy neonates. This case illustrates a diagnosis of an extremely rare single gene disorder in the pregnancy of a non-consanguineous German couple, providing further evidence toward arthrogryposis with other anomalies as a recessive disease associated with NEK9 gene mutations. Finally, this case demonstrates whole exome sequencing as a valuable adjunct tool for investigating etiology when multiple fetal anomalies are identified without diagnosis on more standard tests.