Expanding the genotype–phenotype correlation in subtelomeric 19p13.3 microdeletions using high resolution clinical chromosomal microarray analysis

Abstract

Structural rearrangements of chromosome 19p are rare, and their resulting phenotypic consequences are not well defined. This is the first study to report a cohort of eight patients with subtelomeric 19p13.3 microdeletions, identified using clinical chromosomal microarray analysis (CMA). The deletion sizes ranged from 0.1 to 0.86 Mb. Detailed analysis of the patients' clinical features has enabled us to define a constellation of clinical abnormalities that include growth delay, multiple congenital anomalies, global developmental delay, learning difficulties, and dysmorphic facial features. There are eight genes in the 19p13.3 region that may potentially contribute to the clinical phenotype via haploinsufficiency. Moreover, in silico genomic analysis of 19p13.3 microdeletion breakpoints revealed numerous highly repetitive sequences, suggesting LINEs/SINEs-mediated events in generating these microdeletions. Thus, subtelomeric 19p13.3 appears important for normal embryonic and childhood development. The clinical description of patients with deletions in this genomic interval will assist clinicians to identify and treat individuals with similar deletions.

Underlying genetic factors of the VATER/VACTERL association with special emphasis on the “Renal” phenotype

“…These include: (i) deletions of 5q11.2 [25], 6q [26], 7q35-qter [27], distal 13q [28,29], 19p13.3 [30], and 20q13.33 [31]; (ii) duplications on 1q41, 2q37.3, and 8q24.3 [32], 9q [33] and at 22q11.21 [34]; (iii) deletion at Yq with duplication at Yp [35], and deletion of 9p24.3-p24.1 with duplication of 18q12.3-q23 [36]; (iv) supernumerary der(22) syndrome [37]; (v) mosaicism for supernumerary ring chromosome 12 [38] or 18 [39]; and (vi) partial monosomy 16p13.3pter/partial trisomy 16q22qter [40]. The smallest of these microaberrations was identified in the study by Hilger et al [32], describing a de novo microduplication at 2q37.3 with an estimated size of 25kb.…”

PIAS4 is associated with macro/microcephaly in the novel interstitial 19p13.3 microdeletion/microduplication syndrome

“…1 However, only a few disease-associated microdeletion/duplication regions have been described. [2][3][4][5][6][7][8][9][10][11] On the short arm, microdeletion/duplication syndromes have been proposed for 19p13. 13, 2 19p13.12 3 and terminal 19p13.3 microdeletions.…”

Prader-Willi Syndrome due to an Unbalanced de novo Translocation t(15;19)(q12;p13.3)

“…Our patient had marked cognitive delays, seizures and ADHD in addition to the typical features of PWS including hyperphagia and skin picking but not hypogonadism/hypogenitalism or hypopigmentation, as the OCA2 gene in the 15q11-q13 region was not deleted. Peutz-Jeghers disease associated with deletion of STK11 on chromosome 19p13.3 [Peddibhotla et al, 2013] was not present in our patient as this gene was not deleted. Hence, our patient with a translocation involving the 15q11-q13 region did not have a recognized deletion of the 19p13.3 band detectable with a high resolution SNP microarray using standard genome filter parameters.…”