title: 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.
authors.affiliation: Department of Molecular Medicine, Medical Genetics, University of Pavia, Pavia, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Gana
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Veggiotti
authors.forename: Giusy
authors.initials: G
authors.lastname: Sciacca
authors.forename: Cristina
authors.initials: C
authors.lastname: Fedeli
authors.forename: Anna
authors.initials: A
authors.lastname: Bersano
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Micieli
authors.forename: Mohamad
authors.initials: M
authors.lastname: Maghnie
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccone
authors.forename: Elena
authors.initials: E
authors.lastname: Rossi
authors.forename: Katie
authors.initials: K
authors.lastname: Plunkett
authors.forename: Weimin
authors.initials: W
authors.lastname: Bi
authors.forename: Vernon R
authors.initials: VR
authors.lastname: Sutton
authors.forename: Orsetta
authors.initials: O
authors.lastname: Zuffardi
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000293:Adolescent; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002872:Chromosome Deletion; D002888:Chromosomes, Human, Pair 19; D055028:Comparative Genomic Hybridization; D004268:DNA-Binding Proteins / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics; D019066:Facies; D005260:Female; D057895:Haploinsufficiency; D006801:Humans; D007021:Hypospadias / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D008607:Intellectual Disability / Q000235:genetics; D008297:Male
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C430237:WRNIP1 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities