19q13.11 cryptic deletion: description of two new cases and indication for a role of WTIP haploinsufficiency in hypospadias

Abstract

Developmental delay/intellectual disabilities, speech disturbance, pre- and postnatal growth retardation, microcephaly, signs of ectodermal dysplasia, and genital malformations in males (hypospadias) represent the phenotypic core of the recent emerging 19q13.11 deletion syndrome. Using array-CGH for genome-wide screening we detected an interstitial deletion of chromosome band 19q13.11 in two patients exhibiting the recognizable pattern of malformations as described in other instances of this submicroscopic genomic imbalance. The deletion detected in our patients has been compared with previously reported cases leading to the refinement of the minimal overlapping region (MOR) for this microdeletion syndrome to 324 kb. This region encompasses five genes: four zinc finger (ZNF) genes belonging to the KRAB-ZNF subfamily (ZNF302, ZNF181, ZNF599, and ZNF30) and LOC400685. On the basis of our male patient 1 and on further six male cases of the literature, we also highlighted that larger 19q13.11 deletions including the Wilms tumor interacting protein (WTIP) gene, proximal to the MOR, results in hypospadias making this gene a possible candidate for this genital abnormality due to its well-known interaction with WT1. Although the mechanism underlying the phenotypic effects of copy number alterations involving KRAB-ZNF genes at 19q13.11 has not clearly been established, we suggest their haploinsufficiency as the most likely candidate for the phenotypic core of the 19q13.11 deletion syndrome. In addition, we hypothesized WTIP gene haploinsufficiency as responsible for hypospadias.

Figure 1

Patient 1 at 14 years of age showing dystonic tetraplegia (a) with severe oromandibular impairment (b), thin face, thick eyebrows medially sparse, hypertelorism, columella below alae nasi, thin lips, low set ears with large lobules (b), and cutis aplasia in midline of scalp (c). Patient 2 at 8 years of age showing round face with narrow and up-slanting palpebral fissures, thick eyebrows medially sparse, puffy checks, columella below alae nasi, short philtrum, thin lips, hypodontia with coarse and rudimental shaped teeth (d), small mandible, and large ear lobules (e).

Figure 2

(a) Array-CGH profile of the whole chromosome 19 from patient 1. (b) Array-CGH profile of the whole chromosome 19 from patient 2. (c) Microsatellites analysis in patient 1 and his parents showing the absence of the maternal allele in the proband.

Figure 3

A schematic representation of the overlapping deletions in the two patients and previously reported cases. A close view of chromosome band 19q12-q13.12 is displayed on the top. The comparison of the deleted regions in our patients and previously reported cases narrows down the overlapping critical region from about 750 kb to a size of 324 kb, located on chromosome band 19q13.11, encompassing five genes. WTIP (position: chr19:39 664 720–39 683 925) and SCN1B (position: chr19:40,213,432–40,217,014) are located outside the MOR (chr19: 39 803651–40 127 916).