Pontocerebellar hypoplasia in association with de novo 19p13.11p13.12 microdeletion

• Published in: American journal of medical genetics. Part A 2011-11, Vol.155 (11), p.2871-2878
• Main Authors: Gallant, Natalie M., Baldwin, Erin, Salamon, Noriko, Dipple, Katrina M., Quintero‐Rivera, Fabiola
• Format: Article
• Language: English
• Subjects: 16p13.2; 19p13.11; 19p13.12; 6q24.3; 6q25.1; Abnormalities, Multiple - diagnosis; Abnormalities, Multiple - genetics; array CGH; Autism; Biological and medical sciences; Brain; Brain stem; Central nervous system; Cerebellum; chromosome 16; Chromosome Deletion; Chromosomes, Human, Pair 16 - genetics; Chromosomes, Human, Pair 19 - genetics; Chromosomes, Human, Pair 6 - genetics; DEAD-box RNA Helicases - genetics; Differentiation; Etiology; Fatal Outcome; Female; Fluorescence in situ hybridization; Gene deletion; Genetic screening; Humans; Hypoplasia; In Situ Hybridization, Fluorescence; Infant; Infant, Newborn; Magnetic Resonance Imaging; Medical genetics; Medical sciences; microarray; microdeletion; Midgut; Olivopontocerebellar Atrophies - diagnosis; Olivopontocerebellar Atrophies - genetics; Olivopontocerebellar Atrophies - pathology; Optics; Point Mutation; Polymorphism, Single Nucleotide; pontocerebellar hypoplasia; Pregnancy; Pregnancy Complications - pathology; Rib; RNA helicase; RNA Splicing Factors; RNA-Binding Proteins - genetics; Single-nucleotide polymorphism; Susceptibility; Xenopus laevis
• ISSN: 1552-4825; 1552-4833; 1552-4833
• DOI: 10.1002/ajmg.a.34286

The pontocerebellar hypoplasias (PCHs) are a group of clinically variable disorders characterized by abnormally small cerebellum and brainstem, generally inherited in an autosomal recessive pattern. While PCHs have been grouped into six subtypes, clinical diagnosis is equivocal until a genetic diagnosis is established. We report a patient with PCH, intrauterine growth restriction, ventricular septal defect, rib anomalies, midgut malrotation, and facial dysmorphic features. Using SNP analysis, we identified three de novo deletions of: 1.055 Mb at 6q24.3q25.1 (148174730–149229583); 169 kb at 16p13.2 (6565411–6733934); and 2.530 Mb at 19p13.11p13.12 (13857587–16387798), which were confirmed by FISH. 19p13 deletions are rare aberrations. Of patients previously described with overlapping 19p13.12 deletions and multiple anomalies, only one presented with PCH. Deleted in both that patient and the patient reported here, is DDX39, a DEAD‐box RNA helicase. DDX39 is part of the homeostatic machinery that regulates the switch of cellular proliferation and differentiation. It is highly expressed in the developing central nervous system and optic cup of Xenopus laevis. The brain abnormalities in the patient reported here were more severe than the previously reported patient, which may be due to additional deletions or undetected point mutations in the nondeleted allele. Notably, the patient reported here also has a partial deletion of RBFOX1 (A2BP1), which lies within the autism susceptibility locus on 16p13.2. Our findings suggest chromosomal microarray analysis may be useful in determining etiology of syndromic PCH. © 2011 Wiley Periodicals, Inc.