MEIS2 (15q14) gene deletions in siblings with mild developmental phenotypes and bifid uvula: documentation of mosaicism in an unaffected parent

Abstract

MEIS2 (Meis homeobox 2) encodes a homeobox protein in the three amino acid loop extension (TALE) family of highly conserved homeodomain-containing transcription regulators important for development. MEIS2 deletions/mutations have been associated with cleft lip/palate, dysmorphic facial features, cardiac defects, as well as intellectual disability at a variable severity. Here we report on one familial case that two affected siblings carry the same non-mosaic ~ 423 kb genomic deletion at 15q14 encompassing the entirety of CDIN1 and the last three exons (ex. 10, 11, 12) of the MEIS2 gene, while their unaffected father is mosaic for the same deletion in about 10% lymphocytes. Both siblings presented with mild developmental delay and bifid uvula, while no congenital cardiac abnormalities were identified. The elder sister also showed syncopal episodes and mild speech delay and the father had atrial septal defects. This is the first report showing multiple family members inherit a genomic deletion resulting in a MEIS2 partial truncation from a mosaic parent. Taken all together, this study has important implications for genetic counseling regarding recurrence risk and also points to the importance of offering MEIS2 gene tests covering both point mutations and microdeletions to individuals with milder bifid uvula and developmental delay.

Keywords: Chromosome microarray; Deletion; Developmental delay; Dosage effect; FISH; MEIS2; Mosaicism; Orofacial clefts.

Fig. 1

A familial case of 3′ MEIS2 deletion. a Pedigree of the family with deletion of 3′ MEIS2; black box indicates subject with speech delay and bifid uvula; arrow indicates the proband. b CMA analysis revealed an approximately 423 Kb interstitial deletion of the long arm of chromosome 15 in the proband (II-2). The CDIN1 gene is deleted, and 3′ part of MEIS2, including exons 10, 11, 12 of the NM_170676.5 transcript, is deleted. Colors and locations of FISH probes are indicated. c FISH analysis confirmed the deletion in the proband (II-2) and her brother (data not shown). d, e FISH analysis revealed mosaicism of the same deletion in the father [I-1; d normal metaphase and interphase cells; e abnormal metaphase and interphase cells with del(15)(q14q14)]