Genomic imbalances in patients with a clinical presentation in the spectrum of Cornelia de Lange syndrome

Abstract

BackgroundCornelia de Lange syndrome (CdLS) is a rare autosomal-dominant disorder characterised by facial dysmorphism, growth and psychomotor developmental delay and skeletal defects. To date, causative mutations in the NIPBL (cohesin regulator) and SMC1A (cohesin structural subunit) genes account for > 50% and 6% of cases, respectively.MethodsWe recruited 50 patients with a CdLS clinical diagnosis or with features that overlap with CdLS, who were negative for mutations at NIPBL and SMC1A at molecular screening. Chromosomal rearrangements accounting for the clinical diagnosis were screened for using array Comparative Genomic Hybridisation (aCGH).ResultsFour patients were shown to carry imbalances considered to be candidates for having pathogenic roles in their clinical phenotypes: patient 1 had a 4.2 Mb de novo deletion at chromosome 20q11.2-q12; patient 2 had a 4.8 Mb deletion at chromosome 1p36.23-36.22; patient 3 carried an unbalanced translocation, t(7;17), with a 14 Mb duplication of chromosome 17q24.2-25.3 and a 769 Kb deletion at chromosome 7p22.3; patient 4 had an 880 Kb duplication of chromosome 19p13.3, for which his mother, who had a mild phenotype, was also shown to be a mosaic.ConclusionsNotwithstanding the variability in size and gene content of the rearrangements comprising the four different imbalances, they all map to regions containing genes encoding factors involved in cell cycle progression or genome stability. These functional similarities, also exhibited by the known CdLS genes, may explain the phenotypic overlap between the patients included in this study and CdLS. Our findings point to the complexity of the clinical diagnosis of CdLS and confirm the existence of phenocopies, caused by imbalances affecting multiple genomic regions, comprising 8% of patients included in this study, who did not have mutations at NIPBL and SMC1A. Our results suggests that analysis by aCGH should be recommended for CdLS spectrum cases with an unexplained clinical phenotype and included in the flow chart for diagnosis of cases with a clinical evaluation in the CdLS spectrum.

First Report of Low-Rate Mosaicism for 20q11.21q12 Deletion and Delineation of the Associated Disorder

“…GHRH haploinsufficiency may lead to isolated growth hormone deficiency (GHD) and justify the marked prenatal and postnatal growth retardation found in our patient and in about half of the published cases [Callier et al, 2006;Iqbal and Al-Owain, 2007;Hiraki et al, 2011;Gervasini et al, 2013;Posmyk et al, 2014;Jedraszak et al, 2015]. This hypothesis seems to be supported by the reduced IGF1 levels in our patient.…”

“…Mutations and deletions of SAMHD1 have been associated with systemic lupus erythematosus, and recently homozygous mutations in SAMHD1 were found in 8.3% of Jedraszak et al, 2015Callier et al, 2006Iqbal et al, 2007Hiraki et al, 2011Gervasini et al, 2013Posmyk et al, 2014 Total reported patients Our case (DECIPHER…”

“…To date, 24 unrelated patients have been reported [Fraisse et al, 1981;Petersen et al, 1987;Porfirio et al, 1987;Shabtai et al, 1993;Aldred et al, 2002;Chen et al, 2005;Genevieve et al, 2005;Callier et al, 2006;Borozdin et al, 2007;Iqbal and Al-Owain, 2007;Hiraki et al, 2011;Gervasini et al, 2013;Iourov et al, 2013;Santoro et al, 2013;Posmyk et al, 2014;Jedraszak et al, 2015;Meredith et al, 2017], including 12 with deletions involving the proximal 20q11.2 region [Callier et al, 2006;Iqbal and Al-Owain, 2007;Hiraki et al, 2011;Gervasini et al, 2013;Iourov et al, 2013;Posmyk et al, 2014;Jedraszak et al, 2015;Meredith et al, 2017]. The clinical phenotype shared by these latter patients includes prenatal and postnatal growth retardation, feeding difficulties, psychomotor retardation and intellectual disability of variable degree, craniofacial dysmorphisms (high forehead, frontal bossing, deep-set eyes, midface hypoplasia), and hand/ feet anomalies such as brachydactyly and clinodactyly.…”

Xp11.2 microduplications including IQSEC2, TSPYL2 and KDM5C genes in patients with neurodevelopmental disorders

“…35,36 This is a clinically heterogeneous developmental disorder characterized by malformations affecting multiple systems, including dysmorphic facial features, distal limb defects, cleft palate growth retardation and developmental delay. [35][36][37][38][39][40][41] Mutations in HUWE1 cause XLID with moderate-to-severe ID often coupled with disturbances to speech development. 20,42,43 Of the ID genes in this cluster, HUWE1 is the only one known to be dosage-sensitive, with twofold overexpression in males leading to mild-to-profound cognitive impairment in syndromic XLID, Turner type.…”

Mini-Review Monosomy 1p36 syndrome: reviewing the correlation between deletion sizes and phenotypes

“…Among these, 17 scientific articles met the criteria for inclusion and were selected for this study (D'Angelo et al, 2006;Krepischi-Santos et al, 2006;Kang et al, 2007;Robinson et al, 2008;Bursztejn et al, 2009;El-Hattab et al, 2010;Gajecka et al, 2010;Rosenfeld et al, 2010;Haimi et al, 2011;Mikhail et al, 2011;Nicoulaz et al, 2011;Giannikou et al, 2012;Gervasini et al, 2013;Shiba et al, 2013;Zhu et al, 2013;Shimada et al, 2014;Stagi et al, 2014). Among these, 12 were case reports and five reported series of cases.…”