Interstitial 10p11.23–p12.1 microdeletions associated with developmental delay, craniofacial abnormalities, and cryptorchidism

Abstract

Cryptorchidism is the most common genital problem encountered in males and is associated with many chromosomal disorders; however, the genetic factors are mostly unknown. To delineate critical genes affecting testicular migration, we performed genotype-phenotype correlation in patients with deletions involving the proximal short arm of chromosome 10 (10p11-p12), a rare abnormality characterized by developmental delay, craniofacial abnormalities, and in some cases, cryptorchidism. Here we report on a male patient with developmental delay, mild craniofacial dysmorphism, bilateral cryptorchidism, and an 850-kb deletion, within the 10p11.2 region, involving three genes-MKX, ARMC4, and MPP7-as determined by array comparative genomic hybridization analysis. Comparison with four previously reported male patients with overlapping deletions revealed a 140-kb common region, containing the MKX gene, in association with cryptorchidism. The MKX gene is a member of the three amino acid loop extension (TALE) superclass of homeobox genes that is expressed in developing male gonads (male gonadal ridge and testis cords) in temporal relationship to SOX9, a critical regulator of sexual differentiation. Our results suggest that haploinsufficiency of the MKX gene may affect the developmental process during testis migration or serve as a genetic susceptibility locus for cryptorchidism. We propose that deletions of the proximal 10p represent a contiguous gene syndrome; therefore, patients may present with a complex phenotype, depending on the extent of the deletion.

DeSanto-Shinawi Syndrome: First Case in South America

“…In addition, the patient exhibited ID, behavioral impairment, and feeding difficulties that were also noted in previous cases. However, behavioral abnormalities were less pronounced in our patient than in previously reported patients, and he did not display other major clinical findings [Okamoto et al, 2012;Mroczkowski et al, 2014;DeSanto et al, 2015]. In addition, our patient displayed hypogammaglobulinemia associated with recurrent infections, which to the best of our knowledge has not been previously described.…”

“…3 ). Discussion DESSH is a rare genetic condition caused by loss-offunction mutations in WAC and characterized by motor and speech delays, behavioral abnormalities, and recognizable dysmorphic facial features, including a broad forehead, low nasal bridge, bulbous nasal tip, posteriorly rotated ears, deep-set eyes, brachycephaly as well as hearing and visual abnormalities [Shahdadpuri et al, 2008;Okamoto et al, 2012;Mroczkowski et al, 2014]. In addition, mutations in WAC were described in large cohorts of patients with autism and ID [Okamoto et al, 2012].…”

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

“…35 Interstitial deletions including WAC were previously described and associated with ID. [14][15][16][17] Wentzel et al 14 presented six individuals with an interstitial deletion at 10p12p11, all sharing a region of overlap including two genes: BAMBI and WAC. All individuals were reported to have developmental delay, abnormal behavior and facial dysmorphic features including a bulbous nasal tip, deep set eyes, synophrys/thick eyebrows and full cheeks.…”

“…The shortest region of deletion overlap of the chromosome 10p12p11 contiguous gene deletion syndrome was previously determined by nine deletions ranging in size between 0.99 and 10.66 Mb. [14][15][16][17] Comparison of the deletion in Individual 2 to the shortest region of deletion overlap indicates WAC as a only remaining candidate gene for the ID phenotype (Figure 1b).…”

“…All individuals with a deletion of at least these two genes were reported to have a similar phenotype including ID, behavior problems and dysmorphic features, supporting a disease cause of WAC heterozygous loss-offunction. [14][15][16][17] Although it may well be hypothesized that WAC haploinsuffiency may explain the ID phenotype observed in the 10p12p11 contiguous gene syndrome, and ID in individuals with mutations in this gene, detailed evidence to support this hypothesis is lacking. In the present study we aimed to identify additional individuals with de novo mutations in WAC by using different sequencing strategies to define the clinical spectrum associated with WAC haploinsufficiency.…”