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Recent advances in molecular technology and fetal ultrasound have improved the ability to identify the genetic etiology of fetal anomalies. This is particularly true for fetal skeletal disorders, visualized by prenatal ultrasound. We sought to determine our current diagnostic capability for diagnosing fetal skeletal disorders encountered at a tertiary referral center.
This is a retrospective cohort of singleton fetuses with sonographically detected skeletal disorders identified between December 1, 2014 and April 1, 2016. Cases with significant anomalies of other organ systems, isolated polydactyly and isolated clubfeet were excluded. The following were ascertained: fetal phenotype, genetic testing performed, pregnancy outcome and neonatal phenotype when available.
Of 3863 fetuses evaluated by prenatal ultrasonography over the study period, skeletal findings were ascertained in 88 (2.3%). 59 were excluded for multi-system manifestations, isolated clubfoot or polydactyly. A molecular genetic diagnosis was made in 8 (27.5%) of the remaining 29 cases (Table), including 1 case by whole exome sequencing (WES). A clinical diagnosis was made in 5 (17.2%) additional cases: methotrexate teratogenicity, Russell Silver, pseudoachrondroplasia, achondroplasia and hypophosphatasia (confirmatory testing is pending for the last 2 cases). No clinical or molecular diagnosis was reached for the remaining 16 (55.5%) subjects.
The availability of multiple diagnostic laboratory analyses including: karyotype, microarray, single gene mutation analysis, and multi-gene platforms yields a diagnosis rate of approximately 50% for fetal skeletal anomalies while furthering our clinical acumen in the recognition of phenotypic hallmarks of specific skeletal disorders. A substantial percentage of fetal skeletal disorders, however, remain undiagnosed from a clinical and molecular perspective. Clinical WES, in a variety of formats, is now available. The additive diagnostic performance of clinical WES in the prenatal arena is unclear. Prospective studies with more aggressive molecular evaluation which includes WES are needed to elucidate its role and additive benefit in the workup of fetal skeletal anomalies.