dup(7q)

dup(7q)

Gene 534 (2014) 100–106 Contents lists available at ScienceDirect Gene journal homepage: www.elsevier.com/locate/gene Siblings with opposite chromo...

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Gene 534 (2014) 100–106

Contents lists available at ScienceDirect

Gene journal homepage: www.elsevier.com/locate/gene

Siblings with opposite chromosome constitutions, dup(2q)/del(7q) and del(2q)/dup(7q) Sung Han Shim a,b, Jae Sun Shim c, Kyunghoon Min c, Hee Song Lee c, Ji Eun Park b, Sang Hee Park b, Euna Hwang d, MinYoung Kim c,⁎ a

Department of Biomedical Science, College of Life Science, CHA University, Republic of Korea Genetics Laboratory, Fertility Center of CHA Gangnam Medical Center, CHA University, Republic of Korea Department of Rehabilitation Medicine, CHA Bundang Medical Center, CHA University, Republic of Korea d Department of Plastic and Reconstructive Surgery, CHA Bundang Medical Center, CHA University, Republic of Korea b c

a r t i c l e

i n f o

Article history: Accepted 25 September 2013 Available online 2 October 2013 Keywords: 2q37.2 7q36 Chromosomal abnormality Global developmental delay Intellectual disability Autism

a b s t r a c t Chromosome 7q36 microdeletion syndrome is a rare genomic disorder characterized by underdevelopment of the brain, microcephaly, anomalies of the sex organs, and language problems. Developmental delay, intellectual disability, autistic spectrum disorders, BDMR syndrome, and unusual facial morphology are the key features of the chromosome 2q37 microdeletion syndrome. A genetic screening for two brothers with global developmental delay using high-resolution chromosomal analysis and subtelomeric multiplex ligation-dependent probe amplification revealed subtelomeric rearrangements on the same sites of 2q37.2 and 7q35, with reversed deletion and duplication. Both of them showed dysmorphic facial features, severe disability of physical and intellectual development, and abnormal genitalia with differential abnormalities in their phenotypes. The family did not have abnormal genetic phenotypes. According to the genetic analysis of their parents, adjacent-1 segregation from their mother's was suggested as a mechanism of their gene mutation. By comparing the phenotypes of our patients with previous reports on similar patients, we tried to obtain the information of related genes and their chromosomal locations. © 2013 Elsevier B.V. All rights reserved.

1. Introduction Global developmental delay (GDD), intellectual disability (ID), and autistic spectrum disorder (ASD) are the major reasons of clinical reference for post-natal neurodevelopmental abnormalities in children without any particular event causing brain damage. GDD is a subset of developmental disabilities defined as “significant delay in two or more of the following developmental domains: gross/fine motor, speech/language, cognition, social/personal, and activities of daily living” (Majnemer and Shevell, 1995). ID is an alternative term for mental retardation, which can be Abbreviations: GDD, global developmental delay; ID, intellectual disability; ASD, autistic spectrum disorder; IQ, intelligence quotient; FISH, fluorescent in situ hybridization; MLPA, multiplex ligation dependent probe amplification; VIPR2, vasoactive intestinal peptide receptor 2; GTG, guanine thymine guanine; CGH, comparative genomic hybridization; DNA, deoxyribonucleic acid; der, derivative chromosome; mat, maternal origin; BDMR, brachydactyly mental retardation syndrome; AHO, Albright hereditary osteodystrophy; HDAC4, histone deacetylase 4; WDR60, WD repeat domain 60; SHH, Sonic Hedgehog gene; MNX1, motor neuron and pancreas homeobox 1; CNTNAP2, contactin associated protein-like 2; GPC1, glypican1; GPR35, G protein-coupled receptor 35; FARP2, FERM, RhoGEF and pleckstrin domain protein 2; STK25, Serine/threonine-protein kinase 25; PDC1, pyruvate decarboxylase 1; NRF, National Research Foundation of Korea. ⁎ Corresponding author at: Department of Rehabilitation Medicine, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 463-712, Republic of Korea. Tel.: +82 31 780 1872; fax: +82 31 780 3449. E-mail address: [email protected] (M. Kim). 0378-1119/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.gene.2013.09.093

diagnosed when an intelligence quotient (IQ) is less than 70, according to the definition of the International Classification of Diseases, Version 10 (ICD 10). The prevalence of ID ranges from 1 to 2% in the general population (Durkin, 2002; Maulik et al., 2011). ASD refers to a broader definition of autism including typical autism, pervasive developmental disorder, and high functioning autism affecting 6 to 10 person per a thousand (Williams et al., 2006). Aside from acquired or environmental factors, a variety of inherited or genetic etiologies have been reported as main causes of ID, which can be classified into several groups; large chromosome abnormalities, microdeletions, changes in copy number, and coding abnormalities in single genes (Raymond and Tarpey, 2006). However, a precise cause of ID is identified in only about 50% of cases with moderate to severe ID, and in an even lower proportion for individuals with mild ID (Chelly et al., 2006). Among the possible aberrations in chromosome, submicroscopic rearrangements including microdeletions and microduplications in the subtelomeric regions has been identified with detection rates ranging from 3 to 23% in GDD/ID (Szabo et al., 2010). In the same context, about 10% to 20% of individuals with an ASD have an identified genetic etiology. Co-occurrence of autism with rare genetic syndromes such as Joubert syndrome, Rett syndrome, and Fragile X syndrome is wellknown. In addition, microscopically visible chromosomal alterations have been reported in up to 5% of patients in ASD; the most frequent

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abnormalities are 15q11–q13 duplications, and 2q37, 22q11.2 and 22q13.3 deletions (Abrahams and Geschwind, 2008; Betancur, 2011). Several different techniques including fluorescent in situ hybridization (FISH), multiplex ligation dependent probe amplification (MLPA), and microarrays have been applied to screening of subtelomeric region rearrangements and fine mapping of the gene of interest (Koolen et al., 2004; Le Caignec et al., 2005). We have conducted genetic screening for the patients with GDD, ID, or ASD with standard high resolution chromosomal analysis, MLPA, and microarray-based comparative genomic hybridization. Among these patients, two brothers with subtelomeric abnormalities on the same chromosomal breakpoints; 2q37.2 with deletion–duplication, and 7q35 with duplication–deletion; were discovered. Up to date, relatively large number of phenotypes such as ID, ASD, and holocencephaly has been reported for 2q37 deletion syndrome, while only a few patients of aberrations at 7q36 region were reported. Recently, the importance of VIPR2 has emerged, which is located at the 7q36.3 region (Vacic et al., 2011). Although there are several reports on aberrations of each location, no patient with both regions affected was reported to date. By comparing these two patients with previous reports on regional differences within 2q37.3, we were able to infer the roles and the importance of the genes in these areas.

2. Patients and methods 2.1. Patient 1 An 11-month-old boy presenting GDD was the third child of a 36year-old mother and a 38-year-old father (Fig. 3, pedigree). The parents were healthy and non-consanguineous. His eldest brother, an 8-yearold boy, was diagnosed as ID and ASD, while the second brother, a 5year-old boy, showed typical development. He was born at 38 weeks

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of gestation, weighing 2190 g, by Cesarean section due to intrauterine growth restriction, and there was no history of brain damage (Table 1). He started rolling from supine to prone positions at 7 months, and creeping at 9 months, indicating gross motor development delay. At 26 months of age, he still crept forward and was unable to sit alone. Anthropometric assessment showed less than 1st percentile of height, weight, and head circumference at 11 month-old and 26 month-old follow-ups. Clinical features such as plagiocephaly, dysmorphic facial features with large, prominent ears, overlapping toes, and residual penile chordee were observed (Fig. 1). Hypotonia in the trunk and proximal limb girdles with hypertonia in the distal lower extremities was examined. There were not autistic traits. He could not produce any meaningful words until 26 months of age, and used only gestures for expression of affirmation or denial. On a routine ophthalmologic examination, retinal detachment with vitreous hemorrhage in the left eye was revealed, which required laser surgery. Magnetic resonance imaging (MRI) of the brain showed delayed myelination in the brain with abnormal T2 hyperintensities and white matter volume loss. 2.2. Patient 2 On the other hand, his eldest brother, 9 years and 4 months old, showed severe autistic features along with GDD and ID. He was born at 40 weeks of gestation with a birth weight of 3.0 kg by Cesarean section due to shoulder dystocia. On birth, he was kept in a neonatal intensive care unit for a week to manage a meconium aspiration. Neonatal brain ultrasonography showed no abnormality. Delayed motor development was apparent as he was unable to walk independently before 36 months of age. He had not been able to produce any meaningful words until 9 years and 4 months. Being easily distracted, indifferent to others, and unable to communicate, the parents took him to a psychiatry department at 5 years of age, and he was diagnosed with autism. Anthropometric assessment showed less than 1st centile of height,

Table 1 Clinical characteristics of the patients. Patient

Patient 1

Patient 2

Chromosomal defect Prenatal history Perinatal history

2q37.3 duplication, 7q35 deletion IUGR, bilateral hydronephrosis 38 weeks, 2.19 kg, C/sec

2q37.3. deletion, 7q35 duplication

Age at clinical diagnosis of GDD Age at genetic diagnosis Age at developmental evaluation Anthropometry Head Face

11 months 11 months 26 months Wt b 1%, Ht b 1%, OFC b 1% Microcephaly, plagiocephaly Round face, epicanthal fold, upslanting palpebral fissures, wide nasal bridge, broad nasal tip Retinal detachment with vitreous hemorrhage Narrow openings of the right external acoustic meatus without intertragic notch Proximal displacement of the 3rd and left 4th toes on the right side Normal echocardiography and sonography Feeding problems, residual penile chordee, hydronephrosis

Eyes Ears Skeletal Cardiac GI/GU Psychiatric Cognition

Significantly delayed 9 month function at 26 months of age

Speech

Meaningless sound and gestures

Motor development

Significantly delayed 6 month function at 26 months of age

Brain-MRI finding

Delayed myelination in the brain with abnormal T2 hyperintensities or white matter volume loss

Medical problem

40 weeks, 3.0 kg, C/sec Amniotic infection, dystocia, meconium aspiration, apnea, cyanosis 12 months 8 years 7 months 9 years 4 months Wt b 1%, Ht b 1%, OFC b 1% Microcephaly Epicanthal fold, small and downslanting palpebral fissures, low nasal bridge Divergent strabismus

Medial deviation of both the 2nd and 3rd toes Normal EKG Micropenis Autism, aggressive behaviors, attention deficit Significantly delayed 8 month function at 9 years of age IQ 13 Receptive language development — 13 months Expressive language development — 10 months Significantly delayed 13 month function at 9 years of age Independent walk at 36 months Subarachnoid cyst in the left cerebellar hemisphere and perimedullary cistern Atopic dermatitis Recurrent infection (pneumonia and otitis media)

C/sec, Cesarean section; GDD, global developmental delay; GI, gastrointestinal; GU, genitourinary; Ht, height; IUGR: intrauterine growth retardation; L, left; OFC, occipitofrontal circumference; OT, occupational therapy; PT, physical therapy; R, right; US, ultrasound; Wt, weight.

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Fig. 1. Clinical features of patient 1. (A) Brachycephaly. (B) Right ear: Mid third ear prominence (remarkable antitragus, concha hypertrophy and narrow cavum concha). Left ear: Shell ear or scaphoid ear deformity (large flattened scapha with diminished helical roll). (C) Anomalies of both feet: dislocation or subluxation of metatarsophalangeal joint (MTPJ) on the right 3 rd toe and left 4th toe. (D) Mongoloid slant of palpebral fissures. (E) Residual midline chordee. (F) Brain MRI: Plagiocephaly.

weight, and head circumference. On physical examination, dysmorphic facial features, anomalies of toes, micropenis, prominent ears, and generalized hypotonia were observed (Fig. 2). According to the Wechsler Preschool and Primary Scale of Intelligence, the full scale IQ of the patient was 13 (b0.1st centile), implying severe ID. The Childhood Autism Rating Scale score was 37.5 suggesting severe autism. He was vulnerable to bacterial infection resulting in pneumonia and otitis media, requiring hospitalization about 3 times a year. He had divergent strabismus in his left eye. Brain MRI detected a subarachnoid cyst in the left cerebellar hemisphere and perimedullary cistern, which was removed through surgery (Fig. 2). 2.3. Chromosome analysis For high-resolution chromosomal analysis, peripheral blood samples from the proband and the family members were drawn and cultured by a standard protocol (Veram and Babu, 1995). Twenty of GTG-banded metaphases were examined and analyzed by the CytoVision version 3.6 (Applied Imaging, UK). 2.4. Genomic DNA extraction and multiplex ligation-dependent probe amplification (MLPA) analysis Genomic DNAs were extracted from peripheral blood samples using the QuickGene DNA Whole blood kit (Fujifilm, Tokyo, Japan) and measured by a NanoDrop® spectrophotometer, ND-1000 (NanoDrop Technologies, Wilmington, DE). To identify whether the patient had a submicroscopic imbalance, the MLPA was performed according to the manufacturer's protocol using the SALSA MLPA P070 Human Telomere-

5 probemix (MRC-Holland, Amsterdam, Netherlands) which contains one probe for each subtelomeric region. The reaction products were loaded on an ABI Prism 3130XL automatic genetic analyzer (Applied Biosystems, Foster City, CA) and analyzed by the GeneMarker v1.95 software (Softgenetics, State College, PA). 2.5. Fluorescent in situ hybridization (FISH) To confirm the MLPA results, FISH analyses were carried out using the locus specific identifier (LSI) probes, TelVysion 2q (spectrum orange) and 7q (spectrum green) (Abbott Laboratories, Abbott Park, IL). All FISH procedures were followed from the manufacturer's protocol. Fluorescent signals were analyzed using a Zeiss AXIO Imager A2 fluorescent microscope with the Isis FISH imaging system version 5.3 (Metasystems, Germany). 2.6. Array-comparative genomic hybridization (CGH) Oligonucleotide-array comparative genomic hybridization (CGH) was performed to characterize the breakpoints and the size of the chromosomal segments. Patients' and reference DNA (Affymetrix, Santa Clara, CA, USA) were labeled with Cy5- and Cy3-dyes, respectively, and prepared for hybridization with a 44 K human CytoScan™ HD array chip (Affymetrix, Santa Clara, CA, USA). All procedures, including DNA labeling, purification, hybridization and post-hybridization washing, were carried out according to the manufacturer's instructions. The arrays were scanned using the GeneChip® 3000 Scanner and data extraction and normalization was performed using the Affymetrix Chromosome Analysis Suite (ChAS) v1.2 Software, respectively. Array

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Fig. 2. Clinical features of patient 2. (A) Dysmorphic facial features with epicanthal fold, small and downslanting palpebral fissures, low nasal bridge and strabismus. (B) Medial deviation of the 2nd and 3rd toes of both feet. (C) Brain MRI. (D) Micropenis. (E) Prominent ears with antihelix underdevelopment. Rt., right; Lt., left.

data were analyzed using the UCSC human genome browser — h19 assembly.

3. Results Chromosome analysis of the proband showed apparently a normal male karyotype, however, MLPA analysis using a subtelomeric probe set (P070) showed unbalanced chromosome constitutions, a trisomy 2q and a monosomy 7q. On the other hand, patient 2 showed a reciprocally different abnormality from the proband analysis; a monosomy 2q and a trisomy 7q. Chromosomal and MLPA analysis for both parents were apparently normal. FISH analysis confirmed that the proband study results in both patients by showing unbalanced derivative chromosomes, der(7) and der(2), respectively, and the mother was found to be a balanced translocation carrier, t(2;7)(q37;q35) (Fig. 3). According to the array-CGH study, the proband of patient 1 had about 3 Mb-gain at 2q37.3–2qter and about 13 Mb-loss at 7q35– qter and the patient 2 showed a reverse pattern, 3 Mb loss of 2q and 13 Mb gain of 7q at the same locations (Fig. 4). Thus, the karyotype of the patient 1 was 46,XX,der(7)t(2;7)(q37.3;q35) mat. ish der(7)t(2;7)(D2S447+,VIJyRM2000−).arr 2q37.3q37.3 (239709268– 242783384) × 3, 7q35q36.3(146125161–159119707) × 1 (Table 2).

4. Discussion In 1999, Temple et al. (1999) reported a case on similar patient. The mother carrying a balanced reciprocal translocation with breakpoints at 2q37.2 and 7q35 passed on unbalanced chromosomes, partial monosomy of 2q37.2 and trisomy of 7q35 to her son. The patient had congenital heart disease, post-axial polydactyly, iris hypoplasia, dysmorphic face, GDD, and prominent midline chordee of external genitalia. In our report, the mother had balanced translocation in her chromosomes as well, and passed on unbalanced chromosomes to her children. The chromosomal constitutions of the two affected children are an example of the possibility of a balanced translocation in parents with an abnormal child. Their opposite chromosome abnormalities were results of adjacent-1 segregations of translocated chromosomes during meiosis I (Fig. 5). There are quite a number of reports on genetic abnormalities on chromosome 2q37, especially deletion of 37.2 and 37.3. Our patient 2 has a lot of symptoms in concordance to the reports with features of ID, facial dysmorphism, and autistic behavior. Deletion of 2q37.3 region is associated with brachydactyly mental retardation (BDMR) syndrome, of which HDAC4 is known to be the critical gene for the clinical features, including facial dysmorphism, developmental delay, cardiac septal defect, autism spectrum disorder, and type E brachydactyly (Williams et al., 2010). HDAC4 is within the

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A

Patient 2 (8 yr 7 mo, follow-up: 9 yr 4 mo)

Patient 1, proband (10 mo, follow-up: 26 mo)

B

2.5

2.5

Normal

1.5 1

0

0 300

Size (bps)

400

500

2

1 0.5

200

Chr 7q36.3

1.5

0.5

100

2.5

2

Peak Ratio

Peak Ratio

2

Peak Ratio

C

Chr 2q37.2

1.5 1 0.5

Chr 2q37.2 100

200

300

Size (bps)

Chr 7q36.3

0 400

500

100

200

300

400

500

Size (bps)

D

Fig. 3. A pedigree of the family (A) and the results of chromosome analyses. The chromosome abnormalities were hardly identified by high-resolution GTG-banding method (B). MLPA results showed a normal pattern in the mother (I-2) and unbalanced chromosome constitutions in patient 1 (II-3) and patient 2 (II-1) (C). FISH results confirmed the MLPA results. Mother had a balanced reciprocal translocation between chromosomes 2 and 7. Patient 1 showed a partial trisomy 2q and a partial monosomy 7q and patient 2 was vice versa (D).

Fig. 4. The results of oligonucleotide array-CGH. Patient 1 (A) showed gain of 2q37.2–qter and loss of 7q35–qter and patient 2 (B) showed reverse pattern, loss of 2q and gain of 7q.

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Table 2 Summary of array CGH results of the proband (II-3). Patient

Chromosome region

Start

End

No. of probes

Size (kb)

Gain/loss

OMIM gene

II-3

2q37.3–2qter 7q35–7qter

239709268 146125161

242783384 159119707

2797 15784

3074.116 12994.55

Gain Loss

HDAC4, CAPN10, AGXT, D2HGDH CNTNAP2, KCNH2, NOS3, PRKAG2, DPP6, EN2, SHH, LMBR1, MNX1, VIPR2

deleted region of our patient 2, which may have caused developmental delay, autistic features, and facial abnormalities. Type E brachydactyly, with a penetration rate of 50–60% in BDMR patients (Aldred et al., 2004; Falk and Casas, 2007), was not observed in our patient. Autistic behaviors, which may occur in association to terminal deletions with breakpoints at any sub-band of 2q37 (Falk and Casas, 2007), was reported to have a penetration rate of 24 to 35% in 2q37 deletion patients (Aldred et al., 2004; Casas et al., 2004), as in the case of our patient 2. Lehman et al. (2001) reported a patient with a variant of holoprosencephaly (HPE) whose cytogenetic analysis revealed a 2q37.1–2q37.3 deletion. Known to be an important locus in forebrain development, damage of this region may lead to brain malformations within the HPE spectrum. A subarachnoid cyst and severe disruption of brain function development in patient 2 might have been affected by the abnormality of this region. In a report on seven generations of a single family, where some members showed an effective monosomy or trisomy for 2q37.3 in cytogenetic analyses, those who were monosomic exhibited various phenotypes with a number of features associated with BDMR syndrome, while those who were trisomic exhibited a phenotypic spectrum ranging from mild facial anomalies and growth retardation to apparent normality (Batstone et al., 2003). Thus, relatively more severe ID and GDD of our patient 2 than those of patient 1 may have been caused by 2q37.3 deletion. A previous study analyzed genotype–phenotype correlations in 14 patients with a 2q37 deletion to suggest candidate genes responsible for facial dysmorphism; GPC1, GPR35, FARP2, STK25 and PDC1 (Leroy et al., 2013). All of these genes were located between 240.6 Mb and 242.7 Mb, which are fully included in the deletion of our patient 2, contributing his abnormal facial features. There are controversies regarding the clinical effect of 7q36 duplication. Duplication of the subtelomeric region of chromosome 7q containing functional genes (FAM62B, WDR60 and VIPR2) can be tolerated without any phenotypic consequences (Bartsch et al., 2007). On the contrary, significant associations of copy number gains at 7q36.3 with schizophrenia and pediatric neurodevelopmental disorders including autism were reported in a previous study, especially to a gene in that region, VIPR2 (Vacic et al., 2011). Therefore, autistic features of our patient

2 may be caused by the 7q35 duplication, rather than the clinical outcome of the 2q37 deletion described above. Several researches on 7q36 deletion and its related genes are available to be referred to. In a study about 4 patients with 7q36 deletions (Horn et al., 2004) which contained the Sonic Hedgehog (SHH) gene and the homeobox gene HLXB9, which is now called the MNX1 gene (Garcia-Barcelo et al., 2009), all the patients showed only minimal manifestations of the HPE spectrum. Similarly, our patient 1 harboring a 7q35 deletion did not exhibit severe structural brain anomalies of the HPE spectrum or common signs of Currarino syndrome, which is mainly caused by mutations in the MNX1 gene (Garcia-Barcelo et al., 2009). However, some microsigns of HPE, such as microcephaly and facial abnormalities were still presented in our patient. The HPE spectrum plausibly resulted from the 7q36.3 breakpoint by dislocating the SHH gene from enhancers that are known to drive expressions in the early forebrain (Lettice et al., 2011). In a mouse and human mutation study, Lmbr1, which is located at 7q36.3, was suggested as a critical gene required for limb formation. Reciprocal changes in levels of Lmbr1 activity led to either increases or decreases in the number of digits in the vertebrate limb (Clark et al., 2001). Among 451 children with unexplained GDD/ID reviewed by Wu et al., a 2year-old girl had a small-sized deletion of 1.53 Mb in 7q36.3 area, which spans the area deleted in our patient 1. She presented with GDD, microcephaly, low hair line, ocular hypertelorism, ptosis, prominent ears and hand malformations. PTPRN2 and NCAPG2 were suggested as their causative genes (Wu et al., 2010). In a previous report (Pavone et al., 2010), a 3-year-old girl showed the typical spectrum of anomalies of the Currarino syndrome with growth impairment, severe microcephaly, facial dysmorphism, sensorineural deafness and decreased serum levels of IGF-1. A de novo 10.3 Mb duplication of 7q34–q35 and an 8.8 Mb deletion on 7q36 were identified in this patient. The latter completely overlapped the deletion of our patient 1, who had no sacral or anorectal anomaly with normal value of serum level of IGF-1 (39.27 ng/ml) and normal hearing function. The differences of the two patients in their clinical features are probably caused by variable expressivity or an incomplete penetrance of haploinsufficiency of the co-existing duplications in each patient. In addition, Engralied 2 (Benayed et al., 2009) and CNTNAP2 (Penagarikano and Geschwind, 2012) genes were suggested to be closely associated to ASD in patients with abnormalities in the 7q36 region. 5. Conclusion

Fig. 5. A schematic diagram of adjacent-1 segregation of the translocations during meiosis I.

In conclusion, autism and severe ID of patient 2 are considered to be mainly due to 2q37.3 deletion with an additive effect of 7q35 duplication. On the other hand, GDD and ID with lesser severity without autism in patient 1 seem to be stemmed from the effect of 7q35 deletion. More severe facial dysmorphism with deformed phalanges came from 7q35 deletion with additive effect of 2q37.3 duplication. Both of our patients had obvious growth retardation, cognition deficiency, language disorder, skeletal defect in the toes and abnormal external genitalia. This implies that both regions on chromosomes play a crucial role in brain development, especially in the formation of the forebrain, phalanges and face. We reported a rare family having two affected children caused by abnormal chromosome segregations of a balanced translocation carrier mother. Based on array-CGH results, we characterized exact genomic regions and genes involved and described possible causes of the

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phenotypes, though the contribution of other genes to the phenotypes is not fully understood and further studies on involved genes still remain. Conflict of interest Nothing to declare. Acknowledgment This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education Science and Technology (2012-0132). References Abrahams, B.S., Geschwind, D.H., 2008. Advances in autism genetics: on the threshold of a new neurobiology. Nat. Rev. Genet. 9, 341–355. Aldred, M.A., et al., 2004. Molecular analysis of 20 patients with 2q37.3 monosomy: definition of minimum deletion intervals for key phenotypes. J. Med. Genet. 41, 433–439. Bartsch, O., et al., 2007. Two independent chromosomal rearrangements, a very small (550 kb) duplication of the 7q subtelomeric region and an atypical 17q11.2 (NF1) microdeletion, in a girl with neurofibromatosis. Cytogenet. Genome Res. 119, 158–164. Batstone, P.J., et al., 2003. Effective monosomy or trisomy of chromosome band 2q37.3 due to the unbalanced segregation of a 2;11 translocation. Am. J. Med. Genet. A 118A, 241–246. Benayed, R., et al., 2009. Autism-associated haplotype affects the regulation of the homeobox gene, ENGRAILED 2. Biol. Psychiatry 66, 911–917. Betancur, C., 2011. Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 1380, 42–77. Casas, K.A., et al., 2004. Chromosome 2q terminal deletion: report of 6 new patients and review of phenotype-breakpoint correlations in 66 individuals. Am. J. Med. Genet. A 130a, 331–339. Chelly, J., Khelfaoui, M., Francis, F., Cherif, B., Bienvenu, T., 2006. Genetics and pathophysiology of mental retardation. Eur. J. Hum. Genet. 14, 701–713. Clark, R.M., et al., 2001. Reciprocal mouse and human limb phenotypes caused by gainand loss-of-function mutations affecting Lmbr1. Genetics 159, 715–726. Durkin, M., 2002. The epidemiology of developmental disabilities in low-income countries. Ment. Retard. Dev. Disabil. Res. Rev. 8, 206–211. Falk, R.E., Casas, K.A., 2007. Chromosome 2q37 deletion: clinical and molecular aspects. Am. J. Med. Genet. C: Semin. Med. Genet. 145c, 357–371.

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