Abstract Details

Title Genetic testing of >1300 patients with cerebral palsy reveals an etiology in one-third of cases, underscoring the need for broad genetic testing and a significant recurrence risk for families.

Topic Child Neurology and Developmental Neurology

Presentation(s) P4 - Poster Session 4 (5:30 PM-6:30 PM)

Poster/Presentation
Number 7-028

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.

Authors/Disclosures
Francisca Millan Zamora, MD (GeneDx) PRESENTER	No disclosure on file
Houda Elloumi, PhD (Genedx)	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Dianalee McKnight, PhD (InVitae)	Dr. McKnight has nothing to disclose.

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