Elsevier

European Journal of Medical Genetics

Volume 48, Issue 3, July–September 2005, Pages 346-352
European Journal of Medical Genetics

Original article
Narrowing the deleted region associated with the 15q21 syndrome

https://doi.org/10.1016/j.ejmg.2005.04.012Get rights and content

Abstract

Interstitial deletions of chromosome 15q, not involving the PWS/AS region, are uncommon and poorly characterized. Few cases defined at the cytogenetic level have been reported with 15q21 deletions and characteristic facial dysmorphisms are present in all them. We report on the molecular characterization by array-CGH of a new patient with a 15q21 deletion and on the redefinition of a second patient previously studied with multicolor banding. The two deletions resulted to be similar and involve about 12 and 8 Mb, respectively. Our study might promote to delineate a better genotype–phenotype correlation associated with 15q21 deletions.

Introduction

Chromosome abnormalities are an important cause of mental retardation, dysmorphisms and congenital anomalies. The molecular characterization of such abnormalities is essential to delineate genotype–phenotype correlations which in turn are fundamental for a correct prenatal counseling and to predict postnatal outcomes of other affected individuals. By now, it is obvious that the way we are approaching chromosome imbalances changed radically since the last year. In fact, the possibility to apply array-CGH in all the cases in which a chromosome imbalance is suspected but not visible, or when a characterization by FISH would be an important effort, is becoming crucial in human genetics and it is opening a new future for cytogenetics [4], [9], [13]. Now, we are able to quickly characterize chromosome imbalances at BAC level and to detect cryptic abnormalities that could not be seen with metaphase-based resolution techniques.

We applied array-CGH with 1 Mb resolution to study a new patient with a cytogenetically visible 15q21 deletion and to redefine the same deleted portion in a patient that has been previously studied by microdissection and multicolor banding. So far, only few cases have been reported with deletions of 15q21–22, but none have been molecularly characterized in order to size the extension of the intervening regions [2], [6], [7], [14]. From these few cases it appears that 15q21 deletion patients do show common features that represent a recognizable phenotype [6]. These features include mental and growth retardation, beak-like nose with hypoplastic alae nasi and a thin upper lip. Additional features, likely depending on the different size of the deleted regions, may be small hands and feet, low hair implantation, low set ears, clinodactyly, hypotonia, microcephaly, and late onset obesity. In two cases genitalia were abnormal: a girl with the absence of secondary sexual development and genital hypoplasia with hypoplastic labia majora [2] or a boy with hooded penis with coronal hypospadias and chordee [14]. The present study is providing the characterization at BAC level of two patients carrying partially overlapping deletions of 15q21. We aim to provide a first molecular characterization of deletions associated with the 15q21 syndrome that might help to delineate a better genotype–phenotype correlation.

Section snippets

Cases report

Patient NB was the first child of healthy unrelated parents, both aged 31. He was a male born by cesarean section after a 39-week normal pregnancy and normal screening of maternal blood. He was small for date with a birth weight of 2.620 g (3 ptl), length of cm 48 (25 ptl), head circumference of cm 33 (–2 S.D.) and severely hypotonic. He showed: hypotonia, dry skin, hoarse cry, high prominent forehead, flat temporal regions, and dolicocephaly. He presented hair with two whorls, thin and arched

Material and methods

Cytogenetic analysis has been performed on G-banded metaphases at a resolution of 450–550 bands using the Olympus AX70 microscope. FISH analysis has been done following conventional protocols as described previously [8]. BAC DNA extraction was done using the PhasePrep BAC DNA kit (Sigma). BAC clones were selected from the human library RPCI-11 according to the UCSC Human Genome Assembly (freeze May 2004). Genotyping of 15q21 polymorphic loci from the DNAs of the patient and the parents was

Results

Case NB GTG-karyotyping revealed the presence of a chromosome 15q21 deletion. Array-CGH was performed with 1 Mb resolution to quickly characterize the extension of the deletion and subsequently FISH analysis was performed to refine the breakpoints. From these investigations, we estimated that the deleted region was about 12.4 Mb from BAC RP11-58N19 to BAC CTD-2330J20 (Table 1), according to the latest UCSC release of the human genome sequence (May 2004). The rearrangement has been ascertained

Discussion

Chromosome 15q has been largely described for deletions affecting patients with the Prader-Willi/Angelman syndrome. Other deletions, rather frequent, may involve the telomeric portion of 15q as a consequence of the formation of ring chromosomes [12]. Less common deletions of chromosome 15 have been reported to involve the interstitial region encompassing bands 15q21–q22 [3], [6], [7], [14]. From the available data, it is plausible to think that a new deletion syndrome is lying within this

Acknowledgments

We are grateful to the M. Rocchi of the Dipartimento di Genetica e Microbiologia, Bari and to the YAC Screening Centre of San Raffaele Biomedical Science Park (Milan) for providing BAC clones. This work was supported by cofin02- and cofin03-MIUR (to O.Z.), cofin04-MIUR (to E.R.), the FIRB 2001(to O.Z.) and the Cariplo Foundation (to O.Z.).

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