1p36 deletion syndrome: Review and mapping with further characterization of the phenotype, a new cohort of 86 patients

Abstract

Chromosome 1p36 deletion syndrome (1p36DS) is one of the most common terminal deletion syndromes (incidence between 1/5000 and 1/10,000 live births in the American population), due to a heterozygous deletion of part of the short arm of chromosome 1. The 1p36DS is characterized by typical craniofacial features, developmental delay/intellectual disability, hypotonia, epilepsy, cardiomyopathy/congenital heart defect, brain abnormalities, hearing loss, eyes/vision problem, and short stature. The aim of our study was to (1) evaluate the incidence of the 1p36DS in the French population compared to 22q11.2 deletion syndrome and trisomy 21; (2) review the postnatal phenotype related to microarray data, compared to previously publish prenatal data. Thanks to a collaboration with the ACLF (Association des Cytogénéticiens de Langue Française), we have collected data of 86 patients constituting, to the best of our knowledge, the second-largest cohort of 1p36DS patients in the literature. We estimated an average of at least 10 cases per year in France. 1p36DS seems to be much less frequent than 22q11.2 deletion syndrome and trisomy 21. Patients presented mainly dysmorphism, microcephaly, developmental delay/intellectual disability, hypotonia, epilepsy, brain malformations, behavioral disorders, cardiomyopathy, or cardiovascular malformations and, pre and/or postnatal growth retardation. Cardiac abnormalities, brain malformations, and epilepsy were more frequent in distal deletions, whereas microcephaly was more common in proximal deletions. Mapping and genotype-phenotype correlation allowed us to identify four critical regions responsible for intellectual disability. This study highlights some phenotypic variability, according to the deletion position, and helps to refine the phenotype of 1p36DS, allowing improved management and follow-up of patients.

Keywords: 1p36 deletion syndrome; chromosomal deletion; genotype-phenotype correlation; monosomy 1p36.

FIGURE 1

Mapping of deletions diagnosed by CMA using UCSC genome browser (build GRCh37/hg19) and OMIM genes included in this region. Blue bars represent Group A deletions (n = 56 patients), yellow bars Group B deletions (n = 11 patients), black bars distal and proximal critical regions described in the literature, orange bars and orange vertical dotted lines critical regions described by Shimada et al., red bars and red translucent vertical lines represent the proposed four MORs: MOR1: 1,619,654‐2,057,167; MOR2: 5,528,518‐6,414,084; MOR3: 10,732,711‐11,718,611; MOR4: 21,035,150‐22,652,664. The lower box shows a zoom on the two smallest deletions excluded from the cohort and the GNB1 gene. CMA, chromosomal microarray analysis; MOR, minimal overlapping region

FIGURE 2

Table of absolute values (a) and graph summarizing the proportions in percent (b, c) of the main clinical signs in all patients (green), Group A (blue), and Group B (yellow). CMP, cardiomyopathy; CVM, cardiovascular malformations; DD, developmental delay; GR, Growth retardation; ID, Intellectual disability; NA, not appropriate; NS, not significant; univ, Univariate, ¥: Fisher's exact tests. * p < .05

FIGURE 3

Four patients with 1p36 deletions. Blue and yellow frames corresponding to Groups A and B, respectively. Patient a (2 years and a half) corresponding to del85, patient b to del62, patient c (1 year) to del2, and patient d to del50: 8 years (d1), 10 years (d2), 15 years (d3)

FIGURE 4

Major candidate genes that may explain the 1p36 deletion syndrome's phenotype in our cohort