Determination of the ‘critical region’ for cat-like cry of Cri-du-chat syndrome and analysis of candidate genes by quantitative PCR

Abstract

Cri-du-chat (CDC, OMIM 123450) is a chromosomal syndrome that results from partial deletions on the short arm of chromosome 5. The clinical features of CDC normally include high-pitched cat-like cry, mental retardation, microcephaly, hypertelorism and epicanthic folds. The cat-like cry is the most prominent clinical characteristic in newborn children and is usually considered as diagnostic for the CDC syndrome. Using a strategy of 'phenotype dissection', the critical region for cat-like cry was mapped to the chromosomal segment 5p15.3 -5p15.2 in previous reports. In this study, the distal breakpoints of two interstitial deletions in two clinical distinctive CDC patients are analysed, one with and one without the catlike cry. Using PCR, the critical region for the cat-like cry is mapped to a short 640 kbp region on chromosome 5p. Genome analysis of this critical region reveals a gene-rich sequence containing five known genes, five putative genes and three spliced EST sequences, altogether 71 predicted exons. Three genes, FLJ25076, a homolog to a ubiquitin-conjugating enzyme UBC-E2, FLJ20303, a nucleolar protein NOP2, which may play a role in the regulation of the cell cycle and MGC5309, a protein with similarity to Nut2, a Drosophila transcriptional coactivator, have been characterized and expression profiles determined by quantitative PCR. These results suggest that one candidate gene, FLJ25076, encodes a ubiquitinconjugated enzyme E2 type, which is locally expressed in thoracic and scalp tissues. The other two genes are expressed uniformly in all tissues tested, which suggest that they are housekeeping genes.

The RNA modification landscape in human disease

“…Numerous genetic birth defects have been associated with mutations in RNA modification enzymes, such as the Cri du chat syndrome (NOP2/NOL1/p120/NSUN1) (Wu et al 2005), the Dubowitz syndrome (NSUN2) (Martinez et al 2012), the Noonan-like syndrome (NSUN2) (Fahiminiya et al 2014), or the William-Beuren syndrome (WBSCR20/WBSCR22/ NSUN5) (Doll and Grzeschik 2001). Furthermore, mutations in RNA modification enzymes have also been shown to cause developmental defects, such as Hutchinson-Gilford progeria syndrome (NAT10) (Larrieu et al 2014), and primordial dwarfism (WDR4) (Shaheen et al 2015).…”

Multigenerational autosomal dominant inheritance of 5p chromosomal deletions

“…The proband in Family III has dysmorphic features, developmental delay, microcephaly, and poor growth, but does not exhibit a cat-like cry. Therefore, the microdeletion in this family does not appear to include the critical region for the cat-like cry in CdCS [Wu et al, 2005]. Recently, Elmakky et al [2014] reported a small terminal deletion (arr[hg19] 5p15.33p15.32(22,178-5,539,182)x1) due to an unbalanced 5;15 chromosomal translocation causing atypical CdCS phenotypes including cat-like cry [Elmakky et al, 2014].…”

“…A more severe phenotype and cognitive impairment were reported to be associated with larger deletions [Wilkins et al, 1983;Cornish et al, 1999]. A number of genotypephenotype correlation studies have been performed allowing for definition of critical regions associated with specific manifestations, such as the region for speech delay at band 5p15.3 [Church et al, 1995], the region for cat-like cry between proximal 5p15.3 and distal 5p15.2 [Overhauser et al, 1994;Gersh et al, 1995;Levy et al, 2002;Wu et al, 2005], and the region associated with dysmorphic features at band 5p15.2 [Overhauser et al, 1994;Church et al, 1995;Gersh et al, 1995;Church et al, 1997;Mainardi et al, 2001]. Multiple chromosomal locations have been implicated in intellectual disability and microcephaly, including 5p15.31 [Rossi et al, 2005], 5p15.2, 5p15.1, and 5p13p14 [Overhauser et al, 1994;Gersh et al, 1995;Mainardi et al, 2001].…”

Inflectional morphology in cri du chat syndrome – A case study

“…CCS is a rare genetic disorder with an estimated incidence between 1:20,000 and 1:50,000 births (Niebuhr, 1978;Wu, Niebuhr, Yang, and Hansen, 2005) and is associated with a partial deletion on the short arm of chromosome 5. The clinical features of CCS include a high-pitched cry in infancy and childhood (Sparks and Hutchinson, 1980;Sohner and Mitchell, 1991), malocclusion, hyperand hypotonia, delayed motor development (Carlin and Fraser, 1990), microcephaly (Niebuhr, 1978), mild-to-profound intellectual disability, including problems with verbal processing (Cornish, Bramble, Munir, and Pigram, 1999), a short attention span, hyperactivity and a stereotypical, aggressive and self-injurious behavioural pattern (Collins and Cornish, 2002).…”