78: Multi-gene NGS panel yields high diagnostic rate of skeletal dysplasias detected by fetal ultrasound

Abstract

Using a multi-gene panel designed for detection of 29 skeletal dysplasias known to manifest in the prenatal period, we aimed to determine (1) the diagnostic rate of the panel and (2) the ultrasound abnormalities that were associated with the highest diagnostic rate. Fetal specimens from 180 pregnancies referred for prenatal diagnosis for suspected skeletal dysplasia following abnormal ultrasound were tested. A custom designed NextGen sequencing panel interrogating the complete coding regions of 22 genes and 1 known pathogenic variant in IFITM5 was used. Of these tested genes, 7 are associated with autosomal dominant inheritance (AD), 12 with autosomal recessive (AR), 2 with AD/AR, 1 X-linked dominant and 1 X-linked recessive. Identification of pathogenic or likely pathogenic variant(s) (P/LP) consistent with gene and disease mechanisms was considered diagnostic. Physician-provided clinical indications were retrospectively reviewed and compared to the outcome of genetic testing. Prenatal testing provided diagnostic results in over half of fetuses (96/180; 53%) with causative variants identified in 10 genes associated with fetal skeletal dysplasias (FGFR3: n=43, COL1A1: n=15, COL1A2: n=11, COL2A1: n=10, SOX9: n=5, SLC26A2: n=4, DYNC2H1: n=3, FGFR2: n=3, EVC2: n=1, LEPRE1: n=1). The most common clinical test indications include short limbs, abnormal ribs/small chest circumference, bowed/fractured bones, and upper limb abnormalities. Of the negative or uncertain cases, 8% (7/84) were positive for concurrent or subsequent diagnostic testing (cytogenomic or whole exome sequencing). The diagnostic yield of our prenatal skeletal dysplasia panel was 53%. Among fetuses with a positive test outcome, 87 of 96 (91%) had an autosomal dominant disorder with 45% (43/96) of these in FGFR3 alone, and 9 of 96 (9%) an autosomal recessive disorder. Although these findings demonstrate genetic heterogeneity, four major ultrasound findings highly correlate with positive results for these distinct disorders. Our findings underscore the clinical utility of a comprehensive, multi-gene sequencing approach in the prenatal diagnosis of skeletal dysplasias.