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.

Keywords: 5p-minus syndrome; Cri du chat; behavior problems; intellectual disabilities; subtelomeric deletion.

FIGURE 1

(A) Facial features of a patient with 5p minus syndrome at age of 6 days, 7 years, 11 years, and 21 years. (B) Details of different ear alterations. (C) Details of several dental anomalies, and of a wide mouth. (D) Details of some hand and finger anomalies. (E) Details of several foot and toe anomalies.

FIGURE 2

Schematic representation of very significant (P ≤ 0.01) inter-correlation among microcephaly and other categoric variables (Kendall’s tau_b analysis was performed).

FIGURE 3

Validation of a GFAP construct by PCA (principal component analysis) statistical approach. Pearson correlation value = 0.846; P = 0.001.

FIGURE 4

Schematic representation of the comparison between subpopulations in 5p- individuals (5p deletions vs. 5p deletion plus additional rearrangements) in the “functional” constructed GFAP (Global functional Assessment of the Patient) and its intermediates (developmental delay items corrected by age, behavioral items, dysmorphic items, communication skills, and comorbidity items). A Student t-test was performed.

FIGURE 5

Schematic representation of the comparison between subpopulations in 5p- individuals (5p deletions vs. 5p deletion plus additional rearrangements) in categoric variables using Kendall’s tau_b statistical analysis. Very significant differences (P ≤ 0.01) were denoted in bold. Circles denote significant differences among variables observed in the 5p deletion group and absent in the 5p deletion + additional rearrangement group.

FIGURE 6

(A) Ward’s hierarchical cluster of the whole cohort by size of the deletions. BIC and AIC determined to be grouped by four clusters. (B) Plot segregation ordered by deletion size in Mb. Every cluster showed the GFAP value. (C) ANOVA analysis for continuous variables or by chi-square test for categoric variables was performed to establish the existence of significant differences between clusters. Further, Bonferroni’s test and z-test for previous significant variables revealed cluster pairs with significant differences among them.

FIGURE 7

Integrative map for clusters shown in Figure 6. Comparisons with previously reported critical regions for phenotype sings at 5p minus syndrome (references refer to clinical symptoms reported in individual families with interstitial deletions in different reported works). Circles represent the areas mapped for the different clusters obtained in Ward’s analysis. Major findings observed in our study are in italic text. Chromosome bands are reported according to ISCN. ID, intellectual disability.