Delineation of 2Q32q35 Deletion Phenotypes: Two Apparent ‘‘Proximal’’ and ‘‘Distal’’ Syndromes
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Hindawi Publishing Corporation Case Reports in Genetics Volume 2013, Article ID 823451, 8 pages http://dx.doi.org/10.1155/2013/823451 Case Report Delineation of 2q32q35 Deletion Phenotypes: Two Apparent ‘‘Proximal’’ and ‘‘Distal’’ Syndromes Adrian Mc Cormack,1 Juliet Taylor,2 Nerine Gregersen,2 Alice M. George,1 and Donald R. Love1,3 1 Diagnostic Genetics, LabPlus, Auckland City Hospital, P.O. Box 110031, Auckland 1148, New Zealand 2 Genetic Health Service New Zealand-Northern Hub, Auckland City Hospital, Private Bag 92024, Auckland 1142, New Zealand 3 School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand Correspondence should be addressed to Donald R. Love; [email protected] Received 14 April 2013; Accepted 22 May 2013 AcademicEditors:P.D.Cotter,S.F.Grant,D.M.Iovannisci,C.Lopez´ Gines,´ and G. Velagaleti Copyright © 2013 Adrian Mc Cormack et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We report on three patients with interstitial deletions of the long arm of chromosome 2 involving bands 2q32.1–q35. They presented with wide-ranging phenotypic variation including facial dysmorphisms, cleft palate, learning difficulties, behavioural issues and severe heart defects. Microarray analysis confirmed an 8.6 Mb deletion in patients 1 and 2 and a 24.7 Mb deletion in patient 3.We discuss the genes involved in the deleted regions including MYO1B, GLS, FRZB, SATB2,andCPS1 and compare the phenotype with those reported in the literature. Taken together, these data suggest that there is a spectrum of disease severity such that patients with deletions encompassing the region of 2q32.1q32.2, which includes the FRZB gene, show an apparently milder phenotype compared to those that lie further distal in 2q32.3q35 that encompasses the SATB2 gene. 1. Introduction region 2q32.1q32.3. Patient 3 carries a 24.7 Mb heterozygous deletion involving the region 2q32.2q35. Interstitial deletions of the long arm of chromosome 2 involving the 2q31q33 region are responsible for a number of 2. Clinical Report clinical features, including facial dysmorphism, developmen- tal delay, failure to thrive, mental retardation, and behavioural 2.1. Patient 1. The proband (patient 1) was the first child disturbances [1, 2]. There have been approximately 40 patients to a nonconsanguineous couple. The antenatal ultrasound described in the literature, but a significant number of these scan was normal at 21-week gestation. At 29 + 4 weeks, cases are not highly resolved, so genotype-phenotype corre- a clot was seen in the ductus arteriosus, resulting in poor lationshavebeendifficulttomake.Morerecently,molecular right ventricular function and hydrops fetalis; no structural karyotyping has allowed high-resolution characterisation of malformations were observed. An amniocentesis was per- these deletions. Van Buggenhout et al. [3] have described four formed and showed a normal male karyotype. The baby was delivered by emergency caesarean section at 29 + 4 weeks. independent patients and reported a recognisable pattern of Despite attempts at resuscitation, the baby died an hour after clinical anomalies. Rifai et al. [4]andCocchellaetal.[1] delivery. Postmortem examination confirmed that there were reported two further cases, with the latter refining a critical no primary malformations and also confirmed almost the region for the syndrome and identifying candidate genes to complete occlusion of the ductus arteriosus by a calcified explain the phenotype [5]. thrombus, suggesting that it had been present for at least The study described here reports on three further cases a few weeks. High-resolution G banded analysis of a blood involving the interstitial region 2q32q35. Patient 1 and her sample taken at the time of delivery showed a karyotype mother, patient 2, carry an 8.6 Mb heterozygous deletion of of 46,XY,del(2)(q32.2q33.1) see Figure 1(a). Parental blood 2 Case Reports in Genetics 25.125.3 25.1 25.3 25.1 25.1 24 24 23 23 22 22 21 21 p 16 16 15 15 14 14 13 13 12 12 11.2 11.2 11.1 11.1 11.1 11.1 11.2 11.2 12 12 13 13 14.1 14.1 14.2 14.2 q 14.3 14.3 21.2 21.1 21.2 21.1 21.3 21.3 22 22 23 23 24.2 24.1 24.2 24.1 24.3 24.3 31 31 32.1 32.1 32.3 2 del(2) 32.2 32.3 33 33 34 35 34 35 36 37.1 36 37.2 37.1 37.3 37.2 37.3 2 del(2) (a) 25.125.3 25.1 25.3 25.1 25.1 24 24 23 23 22 22 21 21 p 16 16 15 15 14 14 13 13 12 12 11.2 11.2 11.1 11.1 11.1 11.1 11.2 11.2 12 12 13 13 14.1 14.1 14.2 14.2 q 14.3 14.3 21.1 21.2 21.2 21.1 21.3 21.3 22 22 23 23 24.2 24.1 24.2 24.1 2 del(2) 24.3 24.3 31 31 32.1 32.2 32.1 32.3 33 35 36 34 37.1 35 37.2 37.3 36 37.1 37.2 37.3 2del(2) (b) Figure 1: G-banded karyotype and corresponding ideogram of chromosomes 2. Panels (a) and (b) show the deleted chromosomes 2 for patients 1 and 3, respectively. The left hand of each panel shows the G-banded chromosomes, and the right side shows the corresponding ideograms. The horizontal black arrows show the location of the deletion breakpoints. samples showed that the abnormality had been maternally buthasnormalwoundhealing.Onexamination,shehad derived (data not shown). significant left-sided hemifacial microsomia, soft and hyper- extensible skin, and evidence of hyperextensible joints. Her 2.2. Patient 2. The mother (patient 2) of the proband (patient teeth and palate were normal. There was no significant family 1) was born with left-sided hemifacial microsomia and history of learning or behavioural difficulties, clefting, or underwent a number of corrective surgical procedures symptoms suggestive of connective tissue disorders. resulting in very limited jaw opening. She had learning difficulties throughout school and a confirmed diagnosis 2.3. Patient 3. Theproband(patient3)wasthefirstchildborn of obsessive compulsive disorder. She reports easy bruising to nonconsanguineous New Zealand Maori parents. There Case Reports in Genetics 3 was a family history of congenital heart disease (coarctation heterozygous deletion involving the interstitial chromo- of the aorta) in a maternal uncle but no other history of some region 2q32.2q35 (hg19 coordinates chr2: 191,306,412- congenital anomalies or intellectual disability. The pregnancy 215,985,530) see Figure 2. was uncomplicated apart from slowing of growth in the third trimester, which was monitored clinically. The child was born 3. Discussion at term by spontaneous vaginal delivery with a birth weight of 2700 g (3rd centile), head circumference 33 cm (5th centile) Interstitial deletions involving the 2q31q33 region have been and crown-heel length 47 cm (5th centile) and Apgar scores described previously. This study examines three additional of eight at 1 and 5 minutes. Soon after birth she developed cases: a familial 8.6 Mb deletion 2q32.1q32.3 in a patient cyanosis in addition to respiratory distress and was admitted with left-sided hemifacial microsomia, learning disability to the neonatal intensive care unit for respiratory support. and psychiatric issues, and a de novo 24.7 Mb deletion of Examination showed dysmorphic features of small palpebral 2q32.2q35 in a patient with heart defects, cleft palate, and fissures, telecanthus, small mouth, cleft palate, micrognathia, significant dysmorphic features. preauricular tags, and minor external ear anomalies. The left hip was unstable. 3.1. Patients 1 and 2. Molecular characterisation showed a Echocardiograms showed a membranous ventricular sep- proximal breakpoint on chromosome 2 at 183 Mb and a distal tal defect, a small secundum atrial septal defect, small PDA, breakpoint at 192 Mb. Cases have been reported previously and severe right ventricular volume overload and persisting with deletions that entirely encompass this deleted region, pulmonary hypertension. Appearances on the cranial ultra- while other cases show varying degrees of overlap with the sound were suggestive of deficiency of the posterior portion deleted region [1, 4–8]seeTable 1. The common clinical of the corpus callosum, but on MRI the corpus callosum features include learning difficulties, facial dysmorphism, and appeared to be normal, and there were no other structural behavioural issues. abnormalities. A renal tract ultrasound was normal. Bilateral The deleted region contains 40 genes (Figure 2), but only cataracts were noted on ophthalmological examination. Hip a few are thought to be clinically significant. There are a ultrasound showed a normal right hip and developmental number of possible candidate genes for the behavioural phe- dysplasia of the left hip. A laryngoscopy and bronchoscopy notype including the GLS gene (OMIM 138280), encoding the were done to investigate stridor and found a short epiglottis. majorenzymeinvolvedinconvertingglutaminetoglutamate. The patient required ongoing intensive care management The significance of this enzyme derives from its possible with continuous positive airway pressure and supplemental implication in behavioural disturbances in which glutamate oxygenduetorespiratoryfailure.Shewasnotabletotolerate acts as a neurotransmitter [9]. In addition, the MYO1B oral feeds and required nasojejunal feeds because of the risk gene (OMIM 606537) encodes a protein that participates in of aspiration. At the age of 10 weeks she underwent cardiac processes critical to neuronal development and function such surgery to repair her ventricular septal defect. as cell migration, neurite outgrowth, and vesicular transport High-resolution G-banded analysis of a peripheral blood [10].