- Case report
- Open Access
- Open Peer Review
Coarctation of the aorta and mild to moderate developmental delay in a child with a de novo deletion of chromosome 15(q21.1q22.2)
© Lalani et al; licensee BioMed Central Ltd. 2006
- Received: 27 May 2005
- Accepted: 10 February 2006
- Published: 10 February 2006
Deletion of 15q21q22 is a rare chromosomal anomaly. To date, there have been nine reports describing ten individuals with different segmental losses involving 15q21 and 15q22. Many of these individuals have common features of growth retardation, hypotonia and moderate to severe mental retardation. Congenital heart disease has been described in three individuals with interstitial deletion involving this region of chromosome 15.
We report a child with coarctation of the aorta, partial agenesis of corpus callosum and mild to moderate developmental delay, with a de novo deletion of 15q21.1q22.2, detected by the array Comparative Genomic Hybridization (CGH). We utilized chromosome 15-specific microarray-based CGH to define the chromosomal breakpoints in this patient.
This is the first description of mapping of an interstitial deletion involving the chromosome 15q21q22 segment using the chromosome 15-specific array-CGH. The report also expands the spectrum of clinical phenotype associated with 15q21q22 deletion.
- Comparative Genomic Hybridization
- Array Comparative Genomic Hybridization
- Interstitial Deletion
- Severe Mental Retardation
- Left Ventricular Outflow Tract Obstruction
Interstitial deletion of chromosome 15q21q22 is an infrequently described chromosomal abnormality. To date, there have been only ten individuals reported, nine with variable deletions involving 15q21 [1–9] and one individual with more distal deletion encompassing the 15q22q25 region . All patients described have moderate to severe mental retardation. The four patients described by Yip et al. , Fryns et al. , Martin et al.  and Liehr et al.  have comparable cytogenetic breakpoints and share common features, including beaked nose, thin upper lip, and mental retardation. Congenital heart disease was described in one patient with 15q21q24 deletion  and two patients with interstitial deletion of chromosome 15q15q21 and 15q15q22 respectively [7, 8]. Here, we describe an individual with deletion of 15q21.1q22.2, coarctation of the aorta and mild to moderate developmental delay.
At a chronological age of 48 months, he is in a regular classroom with children, a year younger than him. He is able to throw and catch a ball, march to a song, and use a spoon. He is not yet able to walk down stairs using alternating feet. He is able to name body parts, identify some shapes. He speaks in simple phrases, understands prepositions, and can follow simple commands. He receives speech therapy for his speech/language delays. His current level of functioning was evaluated based on teacher's assessment of his development across the domains of gross motor, fine motor, social/emotional, speech/language, and functional skills. Using the Learn and Play questionnaire, his level of functioning was broadly assessed between 23–34 month level, depending upon the specific task, reflecting mild delays in some and moderate delays in other areas. His motor skills are estimated to fall at the 25–26 month-old level, reflecting mild to moderate delays in this area. His language skills are slightly more delayed, falling at approximately the 23–24 month level, reflecting moderate delays. Cognitively, he is able to count from 1–10 in a stable sequence (a 34-month skill).
Cytogenetics, Comparative genomic hybridization and FISH analyses
Deletion of 15q21 is an infrequently described chromosomal abnormality. Of the ten reported cases, many have common features of beaked nose, hypoplastic alae nasi, thin upper lip, truncal obesity, growth retardation, hypotonia and moderate to severe mental retardation [[1–3]] (see Additional file 1). Our patient's phenotype included prominent forehead, midface hypoplasia, intermittent strabismus, low set ears, carp-shaped mouth, retrognathia, coarctation of the aorta, partial agenesis of corpus callosum, and mild to moderate developmental delay. Two patients with interstitial deletion of 15q15q21 have also been described with craniosynostosis [7, 9]. Neurological problems including hypotonia and seizures are also seen in many individuals with the deletion of this region of chromosome 15q. Congenital heart defect with septal hypertrophy and dilatation of the aorta and pulmonary artery was described in one patient with the deletion of 15q21q24 , who died at 8 months of age. Another patient in the same report had deletion of 15q22q25 and frequent cyanosis of the extremities with no heart murmur, and died at 2 years of age with severe respiratory illness. Five other patients with comparable interstitial deletion [[1–4, 6] had no evidence of congenital heart disease. Two additional cases with interstitial deletion of chromosome15q15-21 have been described with atrial and ventricular septal defects and Tetralogy of Fallot with septal hypertrophy, respectively [7, 8]. We explored probable hemizygous deletion of a cardiac specific gene within the 15q21.1-q22.2 interval responsible for structural heart defects in these individuals. Within this deletion interval, there are few genes that are known to be expressed in heart, including ARPP-19 , RAB27A , and ADAM10 . The α-tropomyosin gene, TPM1 maps to 15q22.2 and is located within the broader chromosome 15 deletion interval, as suggested by the G-band analysis. Heterozygous point mutations in TPM1, account for <5% cases of familial hypertrophic cardiomyopathy . The phenotype ranges from a benign course to severe hypertrophy with progression to dilated cardiomyopathy [16, 17]. In view of our patient's cardiac phenotype, which included septal hypertrophy and juxtaductal aortic coarctation, TPM1 appeared a good candidate gene to investigate if it was included within the deleted region. Prior to performing the array-CGH, we carried out FISH with RP11-69G7 encompassing the TPM1 gene (Figure 3). We established that TPM1 was not included within the deletion interval and ruled out the deletion of TPM1 gene causing left ventricular outflow tract obstruction observed in this patient. The array-CGH subsequently confirmed that RP11-69G7 maps approximately 4 Mb distal to RP11-50C13, the most telomeric clone deleted on the array-CGH in our patient.
The array CGH refined the interstitial deletion in our patient to 15q21.1-q22.2. Microarray-based Comparative genomic hybridization is a powerful method to detect and analyze genomic imbalances. Array CGH using large insert clones is a very useful tool for detecting microdeletions or duplications that are well below the level of detection on high resolution banded karyotype analysis. We have used chromosome 15-specific microarray to define the 15q breakpoints in this case, thus providing a better opportunity for genotype/phenotype correlations in other similarly affected individuals.
We are grateful to the family of our patient for participating in this study and for providing written consent for publication of this study. The support for this work was provided by the Doris Duke Clinical Scientist Development Award (SRL).
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- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/7/8/prepub
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