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. 2022 Feb;9(2):193-205.
doi: 10.1002/acn3.51506. Epub 2022 Jan 24.

Mendelian etiologies identified with whole exome sequencing in cerebral palsy

Maya Chopra #  1 , Dustin L Gable #  2   3 , Jamie Love-Nichols  4 , Alexa Tsao  5 , Shira Rockowitz  6   7 , Piotr Sliz  6 , Elizabeth Barkoudah  8 , Lucia Bastianelli  9 , David Coulter  8 , Emily Davidson  2   10 , Claudio DeGusmao  8 , David Fogelman  11 , Kathleen Huth  2 , Paige Marshall  8 , Donna Nimec  11 , Jessica Solomon Sanders  12 , Benjamin J Shore  9 , Brian Snyder  9 , Scellig S D Stone  13 , Ana Ubeda  11 , Colyn Watkins  9 , Charles Berde  14 , Jeffrey Bolton  8 , Catherine Brownstein  15 , Michael Costigan  16 , Darius Ebrahimi-Fakhari  6   8 , Abbe Lai  8 , Anne O'Donnell-Luria  6   15 , Alex R Paciorkowski  17 , Anna Pinto  8 , John Pugh  18 , Lance Rodan  8   15 , Eugene Roe  8 , Lindsay Swanson  8 , Bo Zhang  8 , Michael C Kruer  19 , Mustafa Sahin  1 , Annapurna Poduri  8 , Siddharth Srivastava  8
Affiliations

Mendelian etiologies identified with whole exome sequencing in cerebral palsy

Maya Chopra et al. Ann Clin Transl Neurol. 2022 Feb.

Abstract

Objectives: Cerebral palsy (CP) is the most common childhood motor disability, yet its link to single-gene disorders is under-characterized. To explore the genetic landscape of CP, we conducted whole exome sequencing (WES) in a cohort of patients with CP.

Methods: We performed comprehensive phenotyping and WES on a prospective cohort of individuals with cryptogenic CP (who meet criteria for CP; have no risk factors), non-cryptogenic CP (who meet criteria for CP; have at least one risk factor), and CP masqueraders (who could be diagnosed with CP, but have regression/progressive symptoms). We characterized motor phenotypes, ascertained medical comorbidities, and classified brain MRIs. We analyzed WES data using an institutional pipeline.

Results: We included 50 probands in this analysis (20 females, 30 males). Twenty-four had cryptogenic CP, 20 had non-cryptogenic CP, five had CP masquerader classification, and one had unknown classification. Hypotonic-ataxic subtype showed a difference in prevalence across the classification groups (p = 0.01). Twenty-six percent of participants (13/50) had a pathogenic/likely pathogenic variant in 13 unique genes (ECHS1, SATB2, ZMYM2, ADAT3, COL4A1, THOC2, SLC16A2, SPAST, POLR2A, GNAO1, PDHX, ACADM, ATL1), including one patient with two genetic disorders (ACADM, PDHX) and two patients with a SPAST-related disorder. The CP masquerader category had the highest diagnostic yield (n = 3/5, 60%), followed by the cryptogenic CP category (n = 7/24, 29%). Fifteen percent of patients with non-cryptogenic CP (n = 3/20) had a Mendelian disorder on WES.

Interpretation: WES demonstrated a significant prevalence of Mendelian disorders in individuals clinically diagnosed with CP, including in individuals with known CP risk factors.

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Conflict of interest statement

DEF: DEF has received grants from CureAP4 Foundation, CureSPG50 Foundation, BPAN Warriors Foundation, Thrasher Research Fund, NIH/NINDS, Tom Wahlig Foundation, Astellas Pharmaceuticals, Mitobridge Inc., The Manton Center for Orphan Disease Research. Received royalties from Cambridge University Press. Received consulting fees from Alcimed Inc. Received honoraria from International Parkinson and Movement Disorder Society. MCK: MCK has received grant support from PTC Therapeutics; consulting fees from PTC Therapeutics, Aeglea, Merz; participated on board for Aeglea and Merz. AP: AP has received support from the Boston Children's Hospital Translational Research Fund. SS: SS has received grants from NIH/NINDS; consulting fees from GLG, Guidepoint (which connected to a client, Fortress Biotech), Novartis, ExpertConnect, Orchard Therapeutics.

Figures

Figure 1
Figure 1
Research pipeline for exome sequencing analysis in this cohort. [Colour figure can be viewed at wileyonlinelibrary.com]
Figure 2
Figure 2
Proposed framework for consideration of genetic testing in patients with CP. [Colour figure can be viewed at wileyonlinelibrary.com]
See this image and copyright information in PMC

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