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, 15 March 2012, Pages 59-62
Short CommunicationCytogenomic characterization of an unexpected 17.6 Mb 9p deletion associated to a 14.8 Mb 20p duplication in a dysmorphic patient with multiple congenital anomalies presenting a normal G-banding karyotype, , , , , , , , , a Department of Morphology and Genetics, Universidade Federal de S&o Paulo, S&o Paulo, Brazilb Department of Imaging Diagnosis, Universidade Federal de S&o Paulo, S&o Paulo, SP, Brazilc Gynecology and Obstetrics Division, ABC School of Medicine, Santo Andr&, SP, Brazild Department of Pathology, Cytogenomics Laboratory, LIM 03, Universidade de S&o Paulo, SP, BrazilWe describe a female patient with developmental delay, dysmorphic features and multiple congenital anomalies who presented a normal G-banded karyotype at the 550-band resolution. Array and multiplex-ligation probe amplification (MLPA) techniques identified an unexpected large unbalanced genomic aberration: a 17.6 Mb deletion of 9p associated to a 14.8 Mb duplication of 20p. The deleted 9p genes, especially CER1 and FREM1, seem to be more relevant to the phenotype than the duplicated 20p genes. This study also shows the relevance of using molecular techniques to make an accurate diagnosis in patients with dysmorphic features and multiple anomalies suggestive of chromosome aberration, even if on G-banding their karyotype appears to be normal. Fluorescence in situ hybridization (FISH) was necessary to identify a masked balanced translocation in the patient's mother, indicating the importance of associating cytogenetic and molecular techniques in clinical genetics, given the implications for patient management and genetic counseling.Highlights? We studied a patient with G-banding normal karyotype and genomic imbalances. ? Molecular genetics increases the ability in identifying genomic imbalances. ? FISH was essential in identifying the inherited balanced translocation. ? Detailed clinical description is important to genotype-phenotype correlation.AbbreviationsMLPA, multiplex-ligation probe amplification; FISH, Fluorescence in situ hybridization; OFC, Occipital&frontal circumference; MRI, Magnetic resonance imaging; DECIPHER, Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources; OMIM, Online Mendelian Inheritance in ManKeywordsDuplication 20p; Deletion 9p; Array; FISH; MLPA1. IntroductionEtiology identification of intellectual disability and physical dysmorphism represents a constant challenge for clinical geneticists. Since conventional karyotyping often fails to detect submicroscopic chromosomal rearrangements, molecular genetics methods have become a very useful tool that has greatly increased the ability to identify pathogenic genomic imbalances. Array techniques have improved the diagnostic success in patients with intellectual deficiency, dysmorphic features and multiple congenital anomalies, disclosing new microdeletion and microduplication syndromes ().
suggested that the chromosomal microarray technique should be used as the first-tier genetic diagnostic test, instead of G-banded karyotyping, for individuals with unexplained developmental/intellectual disabilities, disorders of the autism spectrum, and congenital malformation anomalies. Here, we report on a patient with developmental delay, dysmorphic features and multiple congenital anomalies, in which G-band chromosome analysis showed a normal 46, XX karyotype. Considering the patient's abnormal phenotype, suggestive of chromosome imbalance, the study was refined by using array and MLPA techniques, and a large 9p deletion associated to a 20p duplication were disclosed. FISH analysis only was able to detect the presence of a masked balanced translocation t(9;20)(p22.2;p12.1) in the patient's mother.2. Clinical reportThe proband, a female, was born at 41 weeks of gestation as the first child of a 20-year-old mother and a 26-year-old non-consanguineous father. Birth weight was 2865 g (3rd&5th centile), birth length and OFC were not reported. The first genetic evaluation was made at the age of six months, and the findings were: weight = 4370 g (& 3rd centile); length = 62 cm (10th centile); OFC = 37 cm (& 3rd centile); microcephaly, trigonocephaly, prominent metopic suture, bitemporal narrowness, arched and sparse eyebrows, ocular hypertelorism, upslanted palpebral fissures, prominent eyes, short nose, long philtrum, microstomia, three superior oral frenula, V-shaped cleft palate, small and posteriorly rotated ears, pre-auricular sinus at left, hypoplastic labia majora and minora, and hypotonia (A and B). Cardiologic evaluation at 2 years of age showed tricuspid valve insufficiency and right atrium enlargement. Skeleton X-ray showed metaphyseal enlargement mainly of the arms, and dislocation of the distal phalanx of the left second toe. A brain MRI confirmed trigonocephaly, further showing early closure of the metopic suture, abnormal grooving of the lateral cisterns, compromising the encephalic and cerebellar parenchyma, and sequels from bleeding in the left temporal operculum. A front-view helicoidal scan revealed a prominent metopic suture consistent with trigonocephaly, besides hypertelorism, upslanted palpebral fissures and prominent eyes (C and D and ). The patient progressed with severe developmental delay and malnutrition, presenting several episodes of diarrhea, seizures, severe hypotonia, recurrent pulmonary infection, and a gastrostomy had to be maintained for feeding. At 3 years and 11 months of age she died of bronchopneumonia.Fig.&1. Patient at ages 6 months (A) and 21 months (B), showing trigonocephaly, prominent metopic suture, bitemporal narrowness, flat occiput, arched and sparse eyebrows, strabismus, ocular hypertelorism, upslanted palpebral fissures, prominent eyes, midface hypoplasia, short nose, depressed nasal bridge, anteverted nares, long phil (C) Helicoidal scan: the front view shows prominent metopic suture, bitemporal narrowness (red arrows), hypertelorism, upslanted palpebral fissure (D) MRI brain scan: a sagittal view shows an enlarged and empty sella turcica (yellow arrow) and thin corpus callosum (green arrow).3. Cytogenetic and molecular studiesMetaphase chromosomes of the patient and her parents, analyzed at a 550 band resolution, showed normal karyotypes. Genomic DNA of the patient was isolated from peripheral blood, using a Gentra Puregene kit (Qiagen Sciences Inc., Germantown, MD, USA). A Multiplex Ligation-dependent Probe Amplification (MLPA) assay was performed, using a P070 Human telomere-5 probemix kit (MRC-Holland, Amsterdam, The Netherlands). The results, analyzed with the GeneMarker software, revealed the presence of one copy of 9p and three of the 20p subtelomere probes (data not shown). A microarray assay was performed, using the Cytogenetics Whole-Genome 2.7 M Array&, and analyzed with the Chromosome Analysis Suite version 1.0.1 software (Affymetrix Inc., Santa Clara, CA, USA), using the March 2006 Assembly (NCBI36/hg18) of the UCSC Human Genome browser (http://genome.ucsc.edu/).
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