Microdeletion of 17q22q23.2 encompassing TBX2 and TBX4 in a patient with congenital microcephaly, thyroid duct cyst, sensorineural hearing loss, and pulmonary hypertension

Abstract

Microdeletions of the long arm of chromosome 17 are being reported with increasing frequency. Deletions of 17q22q23.2 may represent a genetically recognizable phenotype although its spectrum of genomic abnormalities, clinical manifestations, and critical regions are not fully delineated. Isolated reports and small case series suggest that deletions of 17q22q23.2 result in haploinsufficiency of dosage sensitive genes NOG, TBX2, and TBX4, which may be responsible for many aspects of the phenotype. Shared clinical features in this group of patients include microcephaly, prenatal onset growth restriction, heart defects, tracheoesophageal fistula, and esophageal atresia (TEF/EA), skeletal anomalies, and moderate to severe global developmental delay. We describe a female patient who presented with severe congenital microcephaly, thyroglossal duct cyst, sensorineural hearing loss, mild tracheomalacia, abnormal auricles, pulmonary hypertension, developmental delay, and postnatal onset growth delay. She had no TEF/EA or heart defects. Using a high density oligonucleotide microarray, we identified a microdeletion at 17q22q23.2, resulting in the heterozygous loss of several genes, including TBX2 and TBX4 but not NOG. The breakpoints did not lie within known segmental duplications. This case helps to further delineate the critical region for TEF/EA, which is likely confined to the chromosomal region proximal to 17q23.1, and suggests that genes in 17q23.1q23.2 may be associated with thyroglossal duct cysts. The role of TBX2 and TBX4 in pulmonary hypertension warrants investigation.

Molecular and clinical delineation of the 17q22 microdeletion phenotype

“…Symphalangism, dysmorphic facial features and intellectual disability have previously been reported in four 17q22 microdeletion patients 4,[6][7][8] (Table 2). In addition, eight patients with similar phenotype and cytogenetically visible deletions between 17q22 and 17q24 have been reported.…”

“…[25][26][27][28][29] Two previously reported 17q22 microdeletion, patients were intellectually disabled. 7,8 All patients in our study, including patient 6, have intellectual disability and deletions of NOG and C17ORF67. However, all cases harbored deletions of several other dosagesensitive genes outside the region of overlap, making haploinsufficiency of NOG and C17ORF67 unlikely to be the cause of intellectual disability in our patients.…”

“…All patients with 17q23.1q23.2 deletions presented with heart defects, which is not the case with the 17q22 microdeletion patients, except for the above mentioned patient 1 with aortic hypoplasia and the patient reported by Khattab et al 6,30,31 Figure 3 Schematic representation of the size and location of 17q22 microdeletions detected by array-CGH in patients described here (black bars) and previously described patients with similar microdeletions (gray bars). 4,[6][7][8] Displayed and magnified chromosomal region is boxed in red on chromosome 17 at the top. The numbers below represent the genomic distance (in base pairs) from the 17p telomere according to UCSC Genome Browser Build 37/hg19 (2009).…”

“…Eight patients with deletions encompassing 17q22 have been reported previously. [1][2][3][4][5][6][7][8] Four of these were identified using array comparative genomic hybridization (array-CGH) or flourescent in situ hybridization (FISH), 4,[6][7][8] and of these, two involved the NOG gene. 4,8 There have been also three reported patients with NOG-like features, where NOG was considered not to be involved; however, these were assessed using standard karyotyping with poor resolution of breakpoints.…”

Genetic and genomic approaches to pulmonary vascular diseases

“…For example, Gaucher disease has pulmonary hypertension and is reported to response well to the enzyme replacement therapy [34]. In microcephaly thyroid, sensorrineural abnormality, and other mental retendered syndrome that have PH, deletions of TBX2 and TBX4 at human chromosome 17q23.2 were identified [35,36]. Activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) mutation is responsible for hereditary hemorrhagic telangiectasia (HHT) and heritable PAH.…”