Interstitial deletion 2p11.2–p12: Further delineation

Writzl, Karin; Lovrečić, Luca; Peterlin, Borut

doi:10.1002/ajmg.a.33064

Cited by 7 publications

(11 citation statements)

References 4 publications

(7 reference statements)

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“…To date, our patient does not manifest the main features of SPG31, some of which are present in previously reported patients with deletion of 2p11.2-p12 (Tzschach et al, 2009;Writzl et al, 2009). Furthermore, she does not present feet deformities that would seem to be a characteristic in patients with REEP1 mutation (De Bot et al, 2010;Du et al, 2009).…”

Section: Discussionmentioning

confidence: 43%

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Contribution of SNP arrays in diagnosis of deletion 2p11.2–p12

Rocca¹,

Fabretto²,

Faletra³

et al. 2012

Gene

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Section: Discussionmentioning

confidence: 43%

“…The proband is only the fourth case so far reported for which breakpoints of the 2p11.2-p12 deletion have been characterized by molecular methods (Barber et al, 2005;Tzschach et al, 2009;Writzl et al, 2009). This finding makes comparisons between the present phenotype and the previous reported ones difficult to carry out.…”

Section: Discussionmentioning

confidence: 99%

Contribution of SNP arrays in diagnosis of deletion 2p11.2–p12

Rocca¹,

Fabretto²,

Faletra³

et al. 2012

Gene

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“…MIM 613564). [9][10][11][12] All show mild-to-moderate intellectual disability, a very happy disposition, speech delay, delayed motor development and minor facial anomalies such as high forehead, broad nasal bridge and large low set ears (Table 1). Despite the very large size of the del(2)(p11.2p12), the clinical phenotype is relatively mild when compared generally with similar-sized deletions reported in literature.…”

Section: Discussionmentioning

confidence: 99%

“…13,14 HSP-related features were seen in patient 1, the previous patient with the 9.4-Mbp deletion 2 and other patients with REEP1 deletions. 10,11 The age distribution for SPG31 shows a bimodal pattern of o20 and 430 years of age 13,14 leaving a possibility that HSP is not yet manifest in patient 1. Figure 1 Interstitial deletion 2p11.2-2p12 in patients 1 and 2 as identified by high-resolution Cytoscan HD array.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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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.

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“…REEP1 variants are a well‐recognized and comparatively frequent cause of autosomal dominant hereditary spastic paraplegia (HSP) (Zuchner et al., ), an axonopathy that primarily affects upper motor neurons (Fink, ). The vast majority of corresponding mutations are truncating and include whole gene deletions (Beetz et al., ; Writzl, Lovrecic, & Peterlin, ; Zuchner et al., ). A 50% loss of REEP1 function, that is, haploinsufficiency, is thus generally assumed to be the pathomechanism that underlies REEP1 ‐associated HSP.…”

mentioning

confidence: 99%

A nonstop variant in REEP1 causes peripheral neuropathy by unmasking a 3′UTR-encoded, aggregation-inducing motif

et al. 2017

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Single-nucleotide variants that abolish the stop codon ("nonstop" alterations) are a unique type of substitution in genomic DNA. Whether they confer instability of the mutant mRNA or result in expression of a C-terminally extended protein depends on the absence or presence of a downstream in-frame stop codon, respectively. Of the predicted protein extensions, only few have been functionally characterized. In a family with autosomal dominant Charcot-Marie-Tooth disease type 2, that is, an axonopathy affecting sensory neurons as well as lower motor neurons, we identified a heterozygous nonstop variant in REEP1. Mutations in this gene have classically been associated with the upper motor neuron disorder hereditary spastic paraplegia (HSP). We show that the C-terminal extension resulting from the nonstop variant triggers self-aggregation of REEP1 and of several reporters. Our findings support the recently proposed concept of 3'UTR-encoded "cryptic amyloidogenic elements." Together with a previous report on an aggregation-prone REEP1 deletion variant in distal hereditary motor neuropathy, they also suggest that toxic gain of REEP1 function, rather than loss-of-function as relevant for HSP, specifically affects lower motor neurons. A search for similar correlations between genotype, phenotype, and effect of mutant protein may help to explain the wide clinical spectra also in other genetically determined disorders.

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Interstitial deletion 2p11.2–p12: Further delineation

Cited by 7 publications

References 4 publications

Contribution of SNP arrays in diagnosis of deletion 2p11.2–p12

Contribution of SNP arrays in diagnosis of deletion 2p11.2–p12

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

A nonstop variant in REEP1 causes peripheral neuropathy by unmasking a 3′UTR-encoded, aggregation-inducing motif

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