Deep Phenotyping and Genetic Characterization of a Cohort of 70 Individuals With 5p Minus Syndrome

Abstract

Chromosome-5p minus syndrome (5p-Sd, OMIM #123450) formerly known as Cri du Chat syndrome results from the loss of genetic material at the distal region of the short arm of chromosome 5. It is a neurodevelopmental disorder of genetic cause. So far, about 400 patients have been reported worldwide. Individuals affected by this syndrome have large phenotypic heterogeneity. However, a specific phenotype has emerged including global developmental delay, microcephaly, delayed speech, some dysmorphic features, and a characteristic and monochromatic high-pitch voice, resembling a cat’s cry. We here describe a cohort of 70 patients with clinical features of 5p- Sd characterized by means of deep phenotyping, SNP arrays, and other genetic approaches. Individuals have a great clinical and molecular heterogeneity, which can be partially explained by the existence of additional significant genomic rearrangements in around 39% of cases. Thus, our data showed significant statistical differences between subpopulations (simple 5p deletions versus 5p deletions plus additional rearrangements) of the cohort. We also determined significant “functional” differences between male and female individuals.

5p deletion with congenital diaphragmatic hernia: a case report

“…In addition, a case of 5p trisomy with bilateral CDH was recently reported, in which the child died of aspiration pneumonia and paralytic ileus at 17 months of age [ 15 ]. Recently, part of the 5p deletion syndrome has been reported to be associated with rearrangements between different chromosomes, or with a deletion followed by a duplication in 5p, as revealed by microarray [ 3 , 16 ]. However, the reported patient’s microarray could not be conducted, and the rearrangements might be relevant to CDH.…”

“…as cri-du-chat syndrome [Online Mendelian Inheritance in Man (OMIM) number #123450] [ 1 ], and is characterized by total or partial deletion (range 35–55%) of the short arm of chromosome 5 [ 2 ]. The average size of chromosomal loss in the 5p deletion syndrome is reported to be around 20 Mb (0.6–35.0 Mb) [ 3 ]. The breakpoints in most patients have been reported from 5p13 to p15.2 [ 4 ], and the critical region is thought to be 5p15.3–15.2 [ 5 ].…”

“…One of the characteristic features of 5p deletion syndrome in newborns is weak, high-pitched monochromatic crying, which usually disappears in the first year of life. Other features include low birth weight, microcephaly, hypotonia, and severe mental and developmental retardation [ 2 , 3 ]. Most fetuses show sonographic findings including cerebellar hypoplasia, ventricular septal defect, ventriculomegaly, choroid plexus cyst, and nasal bone hypoplasia [ 6 ].…”

Cri du chat syndrome patients have DNA methylation changes in genes linked to symptoms of the disease

“…The severity of symptoms appears correlated to the length of the 5p deletion, but the variability between individuals with similar deletions is surprisingly large. A recent study found 39% of Cri du chat patients have additional genetic rearrangements, but they did not find a strong link between having additional genomic changes and distinct symptoms [5].…”

“…The incidence is between 1 in 15,000 and 50,000 live births, with a higher prevalence for females (66%) than males, but the reason for this is unclear [2][3][4]. A recent deep phenotyping study by Nevado et al [5] defined the most frequent features, symptoms, and comorbidities of the disease by creating a 0-100 score that integrates information about 432 patients from multiple publications. They arrived at the developmental delay (scored 95) and hypotonia (scored 99) as being the two symptoms with the highest scores.…”