In this study, we present two subjects, SMS185 and SMS361, with a del(2)(q23.1). These individuals have a distinct clinical phenotype that includes severe cognitive impairment, seizures, relative obesity, small hands and feet, and mild craniofacial dysmorphism, including one child with microcephaly.
A recent report described two patients with overlapping deletions of this region on chromosome 2 exhibiting a ‘pseudo-Angelman' phenotype.3
Both the subjects in this study tested negative for an abnormal SNRPN
DNA methylation patterning of the 15q11.2 region, which rules out a diagnosis of Angelman syndrome. However, they do have features consistent with the ‘pseudo-Angelman' phenotype described by Jaillard et al
In addition to the report by Jaillard et al
, three other cases of 2q23.1 deletion have been described2, 4, 5
(). The common phenotypes observed in these subjects are severe mental retardation, motor delay, severe language impairment (sometimes accompanied by hoarse voice), behavioral abnormalities (including hyperactivity and inappropriate laughter), postnatal growth retardation, relative obesity, and seizures (). In addition, a distinctive craniofacial phenotype is also apparent that includes small head size, wide and open mouth, a tented upper lip, and prominent incisors (). Skeletal abnormalities include generalized brachydactyly (, ).
The more variable phenotypes between the cases reported here and those in previous studies include craniofacial abnormalities such as brachycephaly and relative hypertelorism (likely associated with microcephaly), as well as eye findings and genital abnormalities. Overall, these individuals with varying overlapping deletions of 2q23.1 present with a very similar global phenotype, which leads us to believe that a common gene(s) might be involved.
It is worthwhile to mention that reported duplications of the 2q23 region are rare and tend to be much larger in size than the deletions described in this and previous reports.13, 14, 15
The reported duplication 2q23 cases presented with craniofacial abnormalities, low set ears, and heart, kidney, genital, skeletal, and neurological abnormalities, resulting in death in early infancy.16
The phenotype observed in dup(2)(q23) further supports a gene dosage as a mechanism and the importance of the genes in this region.
When considering all of the reported deletions involving 2q23.1 (), a critical region emerges that includes a single gene, MBD5
(methyl-CpG binding domain protein 5) is expressed neuronally and likely functions in the regulation of gene expression.17, 18 MBD5
contains a methyl-binding domain, sharing sequence homology to MECP2, which when mutated or deleted, results in Rett syndrome. We have shown in this study that MBD5
, in addition to EPC2
, is haploinsufficient in patient white blood cells and lymphoblastoid cells (), providing further evidence of its role in this syndrome and the need for proper gene dosage for normal development and behavior. We do not, however, rule out the possibility that KIF5C
may contribute to variability or severity of the syndrome. These data, taken together with the previous report of a small deletion within MBD5
indicate that haploinsufficiency of MBD5
is the likely common pathological defect for most features of this syndrome.