A recurrent deletion syndrome at chromosome bands 2p11.2-2p12 flanked by segmental duplications at the breakpoints and including REEP1

Abstract

We identified an identical and recurrent 9.4-Mbp deletion at chromosome bands 2p11.2-2p12, which occurred de novo in two unrelated patients. It is flanked at the distal and proximal breakpoints by two homologous segmental duplications consisting of low copy repeat (LCR) blocks in direct orientation, which have 499% sequence identity. Despite the fact that the deletion was almost 10 Mbp in size, the patients showed a relatively mild clinical phenotype, that is, mild-to-moderate intellectual disability, a happy disposition, speech delay and delayed motor development. Their phenotype matches with that of previously described patients. The 2p11.2-2p12 deletion includes the REEP1 gene that is associated with spastic paraplegia and phenotypic features related to this are apparent in most 2p11.2-2p12 deletion patients, but not in all. Other hemizygous genes that may contribute to the clinical phenotype include LRRTM1 and CTNNA2. We propose a recurrent but rare 2p11.2-2p12 deletion syndrome based on (1) the identical, non-random localisation of the de novo deletion breakpoints in two unrelated patients and a patient from literature, (2) the patients' phenotypic similarity and their phenotypic overlap with other 2p deletions and (3) the presence of highly identical LCR blocks flanking both breakpoints, consistent with a non-allelic homologous recombination (NAHR)-mediated rearrangement.

A 3.9-Mb Deletion on 2p11.2 Comprising the REEP1 Gene Causes Early-Onset Atypical Parkinsonism

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Deletions of 2p11.2-p12 are exceedingly rare with few reported cases. 1,2 Most patients display a mild-to-moderate developmental delay and intellectual disability. Additional manifestations are happy disposition, tendency to obesity, and minor dysmorphic features, such as short stature, prominent forehead, hypertelorism, broad nasal bridge, or large low-set ears.

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An intragenic deletion within CTNNA2 intron 7 in a boy with short stature and speech delay: A case report

“…Clinical manifestations of 2p11.2-p12 deletion in seven patients previously reported and in this case. Barber et al 6 Tzschach et al 3 Writzl et al 7 Rocca et al 4 Stevens et al 8 Silipigni et al 5 Present case mainly in human brain, while it is not significantly expressed in other tissues. However, in the absence of a functional assay we cannot predict if the intronic deletion here identified might influence the correct splicing process as it does not affect any canonical splicing sequence.…”

Screening for REEP1 Mutations in 31 Chinese Hereditary Spastic Paraplegia Families

“…The Netherlands 7.4% in SPAST negative AD HSP (27 families and 110 cases) REEP1 is a causative gene of HSP and distal hereditary motor neuropathy type 5B (15), and REEP1-related diseases also include 2p11.2-2p12 deletion syndrome (16). The extension of the REEP1 protein and mislocalized REEP1 can lead to "toxic gain of function" and result in dHMN (15,17), whereas loss of function may lead to HSP (5)(6)(7).…”