Clinical and cytogenetic characterization of 13 Dutch patients with deletion 9p syndrome: Delineation of the critical region for a consensus phenotype

Abstract

The deletion 9p syndrome is caused by a constitutional monosomy of part of the short arm of chromosome 9. It is clinically characterized by dysmorphic facial features (trigonocephaly, midface hypoplasia, and long philtrum), hypotonia and mental retardation. Deletion 9p is known to be heterogeneous and exhibits variable deletion sizes. The critical region for a consensus phenotype has been reported to be located within a approximately 4-6 Mb interval on 9p22. In the present study, deletion breakpoints were determined in 13 Dutch patients by applying fluorescence in situ hybridization (FISH) and in some specific cases by array-based comparative genomic hybridization (array CGH). No clear genotype-phenotype correlation could be established for various developmental features. However, we were able to narrow down the critical region for deletion 9p syndrome to approximately 300 kb. A functional candidate gene for trigonocephaly, the CER1 gene, appeared to be located just outside this region. Sequence analysis of this gene in nine additional patients with isolated trigonocephaly did not reveal any pathogenic mutations.

Complex rearrangement involving 9p deletion and duplication in a syndromic patient: Genotype/phenotype correlation and review of the literature

“…Typical features of 9p monosomy syndrome such as midface hypoplasia, hypertelorism, long philtrum, anomalous auricles and broad neck are present in our patient, but not micrognathia and up slanting palpebral fissures. Cardiac defects, inguinal hernia and scoliosis, all present in our case, have been rarely observed (Swinkles et al, 2008). Trigonocephaly is considered the most prominent feature of 9p deletion syndrome consensus phenotype.…”

“…Subsequently, efforts to narrow down the critical region have been attempted. Swinkles et al (2008) proposed a 300 kb long critical region in 9p22.3, while Faas et al (2007) and Kawara et al (2006) proposed wider and more distally extending regions in 9p23p22.3 (Fig. 3).…”

“…This 9p24.3 critical region is included in the deletion of our patient, who only shows bilateral cryptorchidism, a mild genital/ gonadal phenotype. Different critical regions have been suggested for the consensus phenotype associated to 9p deletion syndrome (Christ et al, 1999;Faas et al, 2007;Kawara et al, 2006;Swinkles et al, 2008). The first, proposed in 1999 (Christ et al, 1999) is associated with developmental delay/mental retardation, trigonocephaly, midface hypoplasia and long philtrum.…”

“…3 and Table 2) (Al Achkar et al, 2010;Hulik et al, 2009;Swinkles et al, 2008). All show features shared by 9p deletion and 9p duplication syndromes, such as developmental delay, psychomotor retardation, hypotonia and low-set ears, but the manifestation of syndromespecific features is variable and depends on the length of the different genomic regions involved.…”

“…In addition, 9p deletion carriers show variable genital and/or gonadal disorders if XY patients, trigonocephaly, midface hypoplasia, small and up slanting palpebral fissures, long philtrum (Christ et al, 1999;Kawara et al, 2006;Swinkles et al, 2008). Conversely 9p duplication carriers present with microcephaly/ brachycephaly, down slanting palpebral fissures, bulbous nasal tip, short philtrum and short neck (Fujimoto et al, 1998;Jelin et al, 2010;Zou et al, 2009).…”