Ayşegül Ozantürk 1 , 2 , 3 , Erica E. Davis 3 , Aniko Sabo 4 , Marjan M. Weiss 5 , Donna Muzny 4 , Shannon Dugan-Perez 4 , Erik A. Sistermans 5 , Richard A. Gibbs 4 , Köksal R. Özgül 1 , Dilek Yalnızoglu 6 , Esra Serdaroglu 6 , Ali Dursun 1 , Nicholas Katsanis 3
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
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:||delayed gross motor development, wide nasal bridge, thin upper lip vermilion, prominent forehead, pes planus, penile hypospadias, moderately short stature, micropenis, intellectual disability, profound, high, narrow palate, enlarged proximal interphalangeal joints, down-sloping shoulders, clubbing of toes, central hypotonia, cat cry|