DALLAS – A multigene skeletal dysplasia panel detected pathogenic variants in 55% of fetal tissue samples with abnormal ultrasound findings and correctly predicted fetal lethality or viability in 75% of these.
The prenatal skeletal dysplasiatests 23 genes implicated in 29 different clinical syndromes, , said at the meeting sponsored by the Society for Maternal-Fetal Medicine. The panel’s performance in a validation cohort of 280 fetal tissue specimens, said Dr. Vincent, “underscores the clinical utility of a comprehensive, multigene sequencing tool that can aid in the diagnosis of prenatal skeletal dysplasias, allowing physicians to better manage these pregnancies.”
Up to 5 pregnancies per 1,000 are affected by some form of skeletal dysplasia, said Dr. Vincent, a clinical molecular geneticist at GeneDx, which manufactures the test. Early findings are typically picked up on ultrasound; the most frequent include limb shortening, long bone angulation, bowing, or fracture; abnormal bone echogenicity; facial dysmorphism; platyspondyly; chest narrowing and abnormal ribs; and frontal bossing of the fetal skull. However, she noted, it’s not always easy to assign a firm diagnosis based on imaging alone.
“In the prenatal period, clinical diagnosis remains challenging because of lack of availability of high-resolution imaging and lack of experience in interpreting the imaging results. Additionally, these are a genetically heterogeneous group of disorders with overlapping clinical features.”
Thefor this panel comprised 280 specimens. Most (84%) were obtained from amniocentesis; 5% were from chorionic villi sampling, and the remainder were derived from other sources. The median gestational age was 20 weeks and 5 days, but the samples ranged from 5 to 36 weeks’ gestation.
The most common imaging indication for testing was short limbs (87%). Other indications included abnormal ribs or small chest circumference (47%); bowed or fractured bones (28%); leg bowing (27%); upper limb deformity (12%); poly- or syndactyly (5%); and other findings, including facial dysmorphism (23%). About 5% of the samples had a family history of skeletal dysplasia.
The panel returned a positive clinical diagnosis for 55% of the specimens. It could not determine a genetic cause for the observed clinical phenotype in 28%, and the test returned uncertain results in 17%, Dr. Vincent said.
“In these cases, we were uncertain whether the variants we identified caused the clinical features.”
Of the 153 positive cases, 42% were affected by pathogenic variants in the collagen genes of COL1A1, COL1A2, and COL1A3. Variants in the FGFR3 gene (39%) were next most common. FGFR3 is associated with achondroplasia, hypochondroplasia, thanatophoric dysplasia types 1 and 2, SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans), and platyspondylic lethal skeletal dysplasia. Mutations of the SOX-9 gene, responsible for campomelic dysplasia, accounted for 5%. The test also identified nine other genetic variants in small numbers of samples.
“About 90% of the genes were autosomal dominant, indicating they are typically de novo or sporadic,” Dr. Vincent said. “About 10% were autosomal recessive, and just 1% were linked to an X-linked mutation.”
The clinical syndromes identified through these genes included osteogenesis imperfecta and thanatophoric dysplasia (33% each); achondrogenesis and spondyloepiphyseal dysplasia (11%); asphyxiating thoracic dystrophy/short rib polydactyly syndrome and campomelic dysplasia (5% each). The remaining cases were atelosteogenesis, Apert syndrome, Crouzon syndrome, chondrodysplasia punctata, hypochondroplasia, and Ellis-van Creveld syndrome.
The test predicted that 64% of the cases would be lethal. In 26%, viability was uncertain, but 10% – including 5% of the osteogenesis imperfecta cases – could be viable.
“Most lethal cases tended to have several characteristics, including short limbs, abnormal ribs, and bowed or fracture bones,” Dr. Vincent said. “Short limbs were almost five times more common in the lethal cases than in those with variable severity. Abnormal ribs and small chest were five times more frequent in the lethal cases, and bowed or fractured bones were four times more common.”
Among the nonpositive cases, 32% had additional testing. Of these, 8% had cytogenetic or large-array abnormalities, and another 8% were positive for a skeletal dysplasia that was not caused by any of the genes on the test panel.
Dr. Vincent noted that the turnaround time for the test is generally 2-3 weeks.
SOURCE: Vincent L et al. .