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Cold Spring Harb Mol Case Stud. 2016 Mar;2(2):a000703. doi: 10.1101/mcs.a000703.

A t(5;16) translocation is the likely driver of a syndrome with ambiguous genitalia, facial dysmorphism, intellectual disability, and speech delay.

Author information

1
Department of Pediatrics, Metabolism Unit, Hacettepe University, Ankara 06410, Turkey;; Department of Biology, Molecular Biology Section, Hacettepe University, Ankara 06800, Turkey;; Center for Human Disease Modeling, Duke University, Durham, North Carolina 27701, USA;
2
Center for Human Disease Modeling, Duke University, Durham, North Carolina 27701, USA;
3
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA;
4
Department of Clinical Genetics, VU University Medical Center (Amsterdam), NL-1081 HV Amsterdam, The Netherlands;
5
Department of Pediatrics, Metabolism Unit, Hacettepe University, Ankara 06410, Turkey;
6
Department of Pediatrics, Pediatric Neurology Unit, Hacettepe University, Ankara 06410, Turkey.

Abstract

Genetic studies grounded on monogenic paradigms have accelerated both gene discovery and molecular diagnosis. At the same time, complex genomic rearrangements are also appreciated as potent drivers of disease pathology. Here, we report two male siblings with a dysmorphic face, ambiguous genitalia, intellectual disability, and speech delay. Through quad-based whole-exome sequencing and concomitant molecular cytogenetic testing, we identified two copy-number variants (CNVs) in both affected individuals likely arising from a balanced translocation: a 13.5-Mb duplication on Chromosome 16 (16q23.1 → 16qter) and a 7.7-Mb deletion on Chromosome 5 (5p15.31 → 5pter), as well as a hemizygous missense variant in CXorf36 (also known as DIA1R). The 5p terminal deletion has been associated previously with speech delay, whereas craniofacial dysmorphia and genital/urinary anomalies have been reported in patients with a terminal duplication of 16q. However, dosage changes in either genomic region alone could not account for the overall clinical presentation in our family; functional testing of CXorf36 in zebrafish did not induce defects in neurogenesis or the craniofacial skeleton. Notably, literature and database analysis revealed a similar dosage disruption in two siblings with extensive phenotypic overlap with our patients. Taken together, our data suggest that dosage perturbation of genes within the two chromosomal regions likely drives the syndromic manifestations of our patients and highlight how multiple genetic lesions can contribute to complex clinical pathologies.

KEYWORDS:

cat cry; central hypotonia; clubbing of toes; delayed gross motor development; down-sloping shoulders; enlarged proximal interphalangeal joints; high, narrow palate; intellectual disability, profound; micropenis; moderately short stature; penile hypospadias; pes planus; prominent forehead; thin upper lip vermilion; wide nasal bridge

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