Schilbach-Rott syndrome associated with 9q22.32q22.33 duplication, involving the PTCH1 gene

Abstract

Schilbach-Rott syndrome (SRS, OMIM%164220) is a disorder of unknown aetiology that is characterised by hypotelorism, epichantal folds, cleft palate, dysmorphic face, hypospadia in males and mild mental retardation in some patients. To date, 5 families and 17 patients have exhibited this phenotype, and recurrence in two of these families suggests an autosomal dominant inheritance. SRS overlaps with a mild form of holoprosencephaly (HPE), but array-CGH analysis and sequencing of some HPE-related genes (SEPT9, SHH and TWIST) did not reveal any variants in at least one family. Herein, we investigated by array-CGH analysis a 11-year-old female patient and her father, both exhibiting the typical SRS phenotype, disclosing in the daughter-father couple the same microduplication of chromosome 9q22.32q22.33 [arr[hg19]9q22.32(98,049,611_98,049,636)x3,9q22.33 (99,301,483_99,301,508)x3], involving eight genes, including PTCH1. The duplication segregated with the disease, since it was not found in the healthy paternal grandparents of the proband. The gain-of-function variants of the PTCH1 gene are responsible for a mild form of HPE. This is the first genetic variant found in SRS. This finding reinforces the hypothesis that SRS belongs to the HPE clinical spectrum and suggests to perform array-CGH in patients with SRS phenotype and, if negative, to consider a potential benefit from sequencing of HPE-related genes.

Fig. 1

a, b Father of the proband, 40 years old. Note the hypotelorism, short philtrum, beaked, long nose with a notched tip, posteriorly rotated ears, short palpebral fissures and asymmetric face with ptosis of the left eye. c, d Proband, 11 years old. Note the similarity with the paternal phenotype: hypotelorism, short philtrum, long nose, small mouth with surgical scar of labiopalatoschisis, flat midface, posteriorly rotated ears, short palpebral fissures and asymmetric face with ptosis of the left eye

Fig. 2

In the upper figure, the three partial array–CGH profiles of the mother, proband and father show the presence of microduplication in the last two subjects involving the chromosomal region 9q22.32q22.33. In the lower figure, the gene content is illustrated. Please note the presence of the entire PTCH1 gene

Fig. 3

Results of the QPCR performed on exons (ex) 6, 14, 23 of the PTCH1 gene (genomic DNA) in two healthy controls CTRL_A (grey) and CTRL_B (black), paternal grandmother (blue), paternal grandfather (red), proband (green) and her father (purple). Note that duplication of PTCH1 is present only in the father–daughter couple

Fig. 4

Summary of published reports of chromosome 9q duplication (blue rectangles), partially overlapping to ours. The position of PTCH1 is highlighted by the red line. Note that this gene is also involved in smaller duplications