Genome Sequencing Identifies an X-Linked Mimic of Walker-Warburg

Topic:

Translational Research

Poster Number: P241

Author(s):

Karla Salazar, MD, Baylor College of Medicine/Texas Children's Hospital, Moez Dawood, Baylor College of Medicine, Davut Pehlivan, MD, Baylor College of Medicine/Texas Children's Hospital, Richard Gibbs, PhD, Baylor College of Medicine, Farida Abid, MD, Baylor College of Medicine/Texas Children's Hospital, Timothy Lotze, MD, Baylor College of Medicine, Jennifer Posey, MD, PhD, Baylor College of Medicine, James Lupski, M.D., Ph.D., D.Sc., Baylor College of Medicine, Daniel Calame, MD, PhD, Baylor College of Medicine

Background/Objectives:
Walker-Warburg syndrome (WWS) is autosomal recessive congenital muscular dystrophy characterized by muscle weakness, brain migrational malformations including cobblestone lissencephaly, and eye malformations. WWS is a dystroglycanopathy classically associated with genes encoding enzymes involved in dystroglycan glycosylation including POMT1, POMT2, and FKRP. Here, we describe a family with two male siblings with clinical diagnosis of WWS who remained molecularly undiagnosed despite clinical exome sequencing (ES) and chromosomal microarray (CMA), and present the results of research, short-read trio whole genome sequencing (WGS) performed by the Baylor College of Medicine (BCM) GREGoR Research Center.
Results:
A 10-year-old male was diagnosed with WWS due to a constellation of symptoms including hypotonia, muscle weakness, hyperCKemia, optic nerve hypoplasia, retinal coloboma and cobblestone lissencephaly. His brother was similarly affected. Due to the lack of genetic variants in dystroglycanopathy genes identified through clinical testing, the family was enrolled in the BCM-GREGoR research program for research short-read WGS. This identified a hemizygous deep intronic OFD1 variant on the X chromosome, ENST00000340096.1: c.312+414A>G, inherited from his heterozygous mother. Affected brother carried the same hemizygous mutation. The variant is absent from gnomAD v4.1.0 and is predicted to alter splicing (SpliceAI donor gain Δ score 0.98, acceptor gain Δ score 0.57). OFD1 variants lead to a phenotypic spectrum including orofaciodigital syndrome 1 and Joubert syndrome 10. It is often lethal in males, but severely affected males have been reported. In retrospect, the siblings have orofaciodigital syndrome features including brachydactyly, clinodactyly, ulnar deviation, cleft palate, dental deformities, and facial dysmorphology.
Conclusions:
Neuromuscular specialists should consider OFD1 in patients clinically suspicious for WWS with negative genetic testing, especially if family history suggests X-linked inheritance. This case illustrates the potential of WGS combined with SpliceAI annotations to detect pathogenic deep intronic variants in WES negative cases.