Segmental haplosufficiency: transmitted deletions of 2p12 include a pancreatic regeneration gene cluster and have no apparent phenotypic consequences

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

“…Bilateral clubfeet Turned outwards -Varus deformity - 12 whereas a near identical deletion was reported by Rocca et al 9 reciprocal to the deletion is expectable, in similarity with other opposite microdeletions/microduplications. 4,22 Still, 2p11.2-2p12 duplication has not been identified to date in literature or ISCA or DECIPHER databases.…”

“…This fits with previous observations that deletion of the major part of chromosome band 2p12, a gene-poor G-dark band, has minimal phenotypic impact. 12 On the basis of the striking phenotypic resemblance of patients, the identical, non-random breakpoints and the presence of highly identical LCR blocks at both breakpoints, we propose here a previously unrecognised, recurrent 2p11.2-2p12 deletion syndrome.…”

“…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.…”

Deletions of 2q14 that include the homeobox engrailed 1 (EN1) transcription factor are compatible with a normal phenotype

“…It is therefore possible that hemizygosity for these genes is more easily tolerated as suggested for haplosufficient deletions of 2p12. 13 In this context, it is interesting that replacement of En1 with En2 sequences rescues the En-1 mutant phenotype in the mouse 14 and that dosage compensation of En1 by En2 has already been invoked to explain the suppression of the En-1 cerebellar phenotype by a change of genetic background. 9 Human EN1 (NM_001426) and EN2 (NM_001427) are 82% homologous at the mRNA level and, although expression of EN2 is more restricted than that of EN1, upregulation of paralogous loci has been recorded in single gene knockouts in yeast, even when the paralogs are not coexpressed.…”

“…Nevertheless, families 1 and 2 provide further evidence that deletions of regions of low gene density are compatible with a normal phenotype. 13 These results will be added to the Chromosome Anomaly Collection of transmitted imbalances for future reference (www.ngrl.org.uk/Wessex/collection/).…”