Genomic analysis of partial 21q monosomies with variable phenotypes

Abstract

Partial monosomy 21 was recently segregated into three regions associated with variable clinical severity. We describe 10 new patients, all examined by single nucleotide polymorphism (SNP) genotyping and G-banded karyotyping. Cohort A consisted of three patients seen in our medical genetics clinics with partial chromosome 21 monosomies. In two of these patients having terminal deletions (21q22.2-ter and 21q22.3-ter), the breakpoints differed by at least 812 Kb of sequence, containing seven RefSeq genes. A third patient had an interstitial hemizygous loss of 16.4 Mb (21q21.1-q22.11). All three patients had relatively mild phenotypes. Cohort B consisted of seven patients with partial chromosome 21 monosomies who had a greater number of dysmorphic features and some major malformations; SNP genotypes were obtained from the Coriell Genetic Cell Repository. We also collected data on partial monsomy 21 cases from the DECIPHER database. This report of 10 new cases of 21q deletion and review of a total of 36 confirms that deletion of the terminal region is associated with a mild phenotype, but suggests that deletion of regions 1 and 2 is compatible with life and have a variable phenotype perhaps relating more to other genetic and environmental variables than to genes in the interval.

Case Report: Interstitial Deletion 21q22.13-Q22.3 in a Male Patient with Developmental Delay, Holoprosencephaly, Dysmorphic Features, and Multiple Congenital Anomalies

“…It was observed that proximal deletion of 21q is associated with mild or no cognitive impairment and problems with balance [9]. Deletion sizes of 4.86 Mb, 5.68 Mb and 16.4 Mb in three different patients were reported by Roberson et al [1] and 4.9 Mb in another patient by Valetto et al [4] compared to deletion size 9,151 Mb in our patient.…”

“…They suggested that the critical region of deletion lies within 21q22.1-q22.2. More sever phenotypes associated with 21q22 deletion were reported such as intrauterine growth retardation, microcephaly, seizures, corpus callosum abnormalities, eye anomalies, micrognathia, abnormal/dysplastic ears, intellectual disability [1,7,8].…”

“…In contrast to trisomy 21, the most common chromosome aneuploidy, complete monosomy of chromosome 21 is incompatible with life and only segmental monosomy has been reported. Previous reports indicated a wide range of phenotypes ranging from normal to severe phenotypes associated with different sizes of deletions in different positions on chromosome 21q22 [1,2]. The spectrum of phenotypes ranges from normal [2], mild [3] to severe phenotypes associated with multiple congenital malformations, dysmorphic features, seizures and delayed development [4].…”

Inv21p12q22del21q22 and intellectual disability

“…The phenotypic and molecular analysis of patients with partial monosomy 21 has been reported before (Chettouh et al, 1995;Roberson et al, 2011;Valero et al, 1999), but none, as far as we know, were associated to a chromosome pericentric inversion. The majority of these partial monosomies is de novo and reported on cytogenetic level, and only a few are submicroscopic deletions.…”

“…The proband also presents thick and everted vermillion of the upper lip. resulting in phenotypes including intellectual disability, brain dysgenesis, extensive dysmorphic features (microcephaly, short neck, epicanthic folds, flat nasal bridge, low set/malformed ears, highly arched palate, and transverse palmar crease), heart and/or renal defects (Migdalska et al, 2012;Roberson et al, 2011).…”