A novel chromosome 19p13.12 deletion in a child with multiple congenital anomalies

Abstract

We describe a patient with multiple congenital anomalies including deafness, lacrimal duct stenosis, strabismus, bilateral cervical sinuses, congenital cardiac defects, hypoplasia of the corpus callosum, and hypoplasia of the cerebellar vermis. Mutation analysis of EYA1, SIX1, and SIX5, genes that underlie otofaciocervical and/or branchio-oto-renal syndrome, was negative. Pathologic diagnosis of the excised cervical sinus tracts was revised on re-examination to heterotopic salivary gland tissue. Using high resolution chromosomal microarray analysis, we identified a novel 2.52 Mb deletion at 19p13.12, which was confirmed by fluorescent in situ hybridization and demonstrated to be a de novo mutation by testing of the parents. Overall, deletions of chromosome 19p13 are rare.

Fig. 1

Photographs of the subject taken at age 6 months (A), 2 years (B), 6 years (C) and 9 years (D) of age demonstrate tall forehead, telecanthus, ptosis, downsloping palpebral fissures, short nose with anteverted nares, long philtrum, and flattened vermillion border.

Fig. 2

Temporal bone computed tomography scan obtained at age 6 years. 2A. Axial sections through the lateral semicircular canals (LSCC) show asymmetry of the LSCC (arrows), with the right LSCC more bulbous and blunt than the left. 2B. Asymmetry is more obvious on coronal sections through the LSCC (arrows).

Fig. 3

Photographs of the dorsal (A) and ventral (B) surfaces of the hands illustrate brachydactyly and terminal abbreviation of the digits with hypoplastic nails, particularly evident on the thumbs.

Fig. 4

Radiographs of the hands demonstrate reduction in size of all the distal phalanges.

Fig. 5

Chromosome microarray data demonstrating 19p13.1 deletion. [A] Graphic representation. Each dot with vertical line deviating from the mean represents a value corresponding to loss or gain in copy number. In the combined column, data are average with gains to the right and losses to the left. Red circle indicates strong indication of a loss of the clone corresponding to the 19p13.1 region while the black circle indicates a loss of the clone corresponding to 3q29. The latter represents a commonly seen polymorphism. [B] Partial karyotype for chromosome 19 showing subtle differences on the short arm of chromosome 19 as indicated by the arrow. [C] The combined log ratio of −0.317 is significant by T statistics with p value at 0.004 suggesting a deletion in this region. [D] FISH confirmation. Only one red signal is demonstrated for BAC clone RP11-56K21, confirming haploinsufficiency shown by CMA, while the subtelomeric probe (129F16/SP6) located on the distal short arm of chromosome 19 showed a normal hybridization pattern (two green signals).

Fig. 6

The loss on the chromosome 19 at band p13.12 is displayed from Test/Reference ratio data of this patient in a 244K microarray from Agilent. The Agilent aberration detection algorithm detects intervals of consistent high or low log ratios within an ordered set of probes by measuring a set of genomic locations and considering their genomic order to make amplification or deletion calls. [A] ~2.52 mega base loss at 19p13.12 is observed. [B] High-resolution view of the deleted region of the patient as compared to her normal parents indicating this is a de novo event.