Abstract
Objective: To establish the positive diagnostic rate (PDR) of exome sequencing (ES) for patients with cerebral palsy (CP).
Background: CP is a broad diagnostic term encompassing disorders impacting movement and posture caused by changes in the developing brain. CP is a common clinical diagnosis, with an incidence of 1 in 500 births. It has been historically attributed to pre/perinatal complications, however, recent studies suggest that a significant proportion of CP may be due to genetic causes.
Design/Methods: ES results from 1346 patients with CP were retrospectively reviewed.
Results: ES yielded a positive result in 32.7% of cases (440/1346). Testing of a proband concurrently with parents (trio) significantly improved the PDR compared to proband-only testing (35.3% vs. 23.3%, p<0.005). Positive findings were reported in 225 different genes, demonstrating the vast genetic heterogeneity of CP. Causative variants were identified in genes associated with autosomal dominant disorders (AD, 65.7%), autosomal recessive (AR, 20.9%), and X-linked (XL, 13.4%). CTNNB1 (4.1%, 18/440) and KIF1A (1.8%, 8/440) were the most common positive genes in this cohort. Additionally, 12% (53/440) of cases had positive results in recently published disease-associated genes. Trio testing revealed a high de novo rate (71.9%). A significant recurrence risk was revealed in 30% (130/440) of cases: 21% (92/440) had biallelic AR variants, 3% (13/440) were inherited XL, 4% (18/440) were inherited AD, and 1.6% (7/440) were inherited from a mosaic parent.
Conclusions: ES revealed a genetic etiology in almost a third of patients with CP, supporting the use of genetic testing in this group. The high rate of de novo positive findings supports utilizing a trio approach. Genetic testing of patients with CP can inform an accurate recurrence risk, as opposed to the general attributions to complications at birth, and also provide information for prognosis, adjusted therapies, and management options.
Disclosure: Dr. Millan Zamora has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GeneDx. Dr. Elloumi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GeneDx. Dr. Teigen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GeneDx. Dr. Scuffins has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GeneDx Inc. Dr. Torene has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GeneDx. Dr. McKnight has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GeneDx, BioMarin.
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