The phenotype of recurrent 10q22q23 deletions and duplications

Abstract

The genomic architecture of the 10q22q23 region is characterised by two low-copy repeats (LCRs3 and 4), and deletions in this region appear to be rare. We report the clinical and molecular characterisation of eight novel deletions and six duplications within the 10q22.3q23.3 region. Five deletions and three duplications occur between LCRs3 and 4, whereas three deletions and three duplications have unique breakpoints. Most of the individuals with the LCR3-4 deletion had developmental delay, mainly affecting speech. In addition, macrocephaly, mild facial dysmorphisms, cerebellar anomalies, cardiac defects and congenital breast aplasia were observed. For congenital breast aplasia, the NRG3 gene, known to be involved in early mammary gland development in mice, is a putative candidate gene. For cardiac defects, BMPR1A and GRID1 are putative candidate genes because of their association with cardiac structure and function. Duplications between LCRs3 and 4 are associated with variable phenotypic penetrance. Probands had speech and/or motor delays and dysmorphisms including a broad forehead, deep-set eyes, upslanting palpebral fissures, a smooth philtrum and a thin upper lip. In conclusion, duplications between LCRs3 and 4 on 10q22.3q23.2 may lead to a distinct facial appearance and delays in speech and motor development. However, the phenotypic spectrum is broad, and duplications have also been found in healthy family members of a proband. Reciprocal deletions lead to speech and language delay, mild facial dysmorphisms and, in some individuals, to cerebellar, breast developmental and cardiac defects.

Figure 1

Schematic representation of 10q genomic rearrangements identified in the probands. (a) Structure of LCRs located in 10q22.3-q23.2 is shown. Blocks of the same colour and/or pattern denote paralogous sequences. Degree of sequence identity between paralogous sequences ranges from 90.8 to 99.8%. Genomic position (in Mb) is shown on a scale below the LCRs, and corresponds to human reference human genome reference sequence version hg18. (b) Map of deletions predicted by oligonucleotide CGH arrays in patients 1–8 and of previously studied individuals JHU10qDel-01, JHU10qDel-02, UM10qDel-01. Grey bar indicates intact DNA sequence. Red dashed line indicates hemizygous deletion. Grey dashed line denotes the genomic area that contains a breakpoint. Genes located in this genomic region are shown below the diagram of the rearrangements.

Figure 2

Map of duplications predicted by oligonucleotide CGH arrays in patients 9–14. Grey bar indicates intact DNA sequence. Red solid line indicates duplication. Genes located in this genomic region are shown below the diagram of the rearrangements. Genomic position (in Mb) is shown on a scale below the LCRs, and corresponds to human reference human genome reference sequence version hg18.

Figure 3

(A) Photographs of probands 1, 3 and 4 with deletions between LCR3 and LCR4. Proband 1 (a) at 13 years of age; she has upward-slanting palpebral fissures, hypotelorism and low-set ears. Proband 3 (b) at 3 years and 7 months of age; he has dolichocephaly, low-set and prominent ears, hypertelorism, epicanthal folds and a flat midface. Proband 4 (c) at 12 years of age; he has hypertelorism, almond-shaped eyes, low-set ears and full lips. (B) Photographs of patients 9, 10 and 11 with duplications of 10q22.3q23.2. Patient 9 (d) at 9 years of age; he has a triangular face, a broad forehead, upslanting palpebral fissures, slightly deep-set eyes, lateral flaring of eyebrows, prominent ears with thickened horizontal superior helices, a thin upper lip and a smooth philtrum. Sibling patients 10 (e) and 11 (f) show upslanting palpebral fissures, strabismus, hypotelorism, a smooth philtrum and anteverted nares.

Figure 4

Frequency of LCR-mediated microdeletions in cohorts of individuals with MR, multiple congenital anomalies and/or autism (y axis) ^{, , , , , , ,} compared with the size of the unique sequence between LCRs (x axis).^{, , , , ,} WBS, Williams–Beuren Syndrome; PWS, Prader Willi Syndrome; AS, Angelman syndrome; SMS, Smith-Magenis syndrome; VCF, velocardiofacial syndrome. Frequencies of PW/AS and VCF syndromes were corrected for the most common deletion causing these syndromes.