Combined Deletion 18Q22.2 and Duplication/Triplication 18Q22.1 Causes Microcephaly, Mental Retardation and Leukencephalopathy

Gene 523 (2013) 92–98

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Short communication Combined deletion 18q22.2 and duplication/triplication 18q22.1 causes microcephaly, mental retardation and leukencephalopathy

Sylvie Nguyen-Minh a, Katrin Drossel b, Denise Horn c, Imma Rost d, Birgit Spors e, Angela M. Kaindl a,b,f,⁎ a Department of Pediatric Neurology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany b SPZ Pediatric Neurology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany c Institute of Human Genetics, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany d Center for Human Genetics and Laboratory Medicine, Lochhamerstr. 29, 82152 Martinsried, Germany e Department of Pediatric Radiology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany f Institute of Neuroanatomy and Cell Biology, Charité-Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10115 Berlin, Germany article info abstract

Article history: Chromosome 18 abnormalities rank among the most common autosomal anomalies with 18q being the most fre- Accepted 15 March 2013 quently affected. A deletion of 18q has been attributed to microcephaly, mental retardation, short stature, facial Available online 5 April 2013 dysmorphism, myelination disorders, limb and genitourinary malformations and congenital aural atresia. On the other hand, duplications of 18q have been associated with the phenotype of Edwards syndrome. Critical chromo- Keywords: somal regions for both phenotypes are contentious. In this report, we describe the ﬁrst case of an 11-year old male Microcephaly Mental retardation with a combined interstitial duplication 18q22.1, triplication 18q22.1q22.2 and terminal deletion 18q22.2q23 with Leukencephalopathy phenotypic features of isolated 18q deletion syndrome and absence of phenotypic features characteristic of Array CGH Edwards syndrome despite duplication of the suggested critical region. This report allows for reevaluation 18q22 of proposed critical intervals for the phenotypes in deletion 18q syndrome and Edwards syndrome. © 2013 Elsevier B.V. All rights reserved.

1. Introduction various authors in order to identify critical regions for the core phenotype of Edwards syndrome. The classic Edwards syndrome with mental Anomalies of chromosome 18 are among the most common autoso- and developmental delay, growth deficiency, craniofacial dysmorphism, mal abnormalities with a duplication of chromosome 18 occurring in ap- clenched hands with overlapping digits and internal organ malformation proximately 1/3600 to 1/10,000 live births (Cereda and Carey, 2012)and is associated with a duplication of the entire chromosome 18 (Binkert a deletion of 18q reported in approximately 1 in 40,000 live births (Cody et al., 1990). However, partial trisomy 18 with mild to severe phenotypes et al., 1999). Distal deletions of 18q are particularly frequent and appear of Edwards syndrome have also been reported (Boghosian-Sell et al., to cause a variable phenotypic spectrum including growth deficiency, 1994; Fryns et al., 1978; Matsuoka et al., 1981; Neu et al., 1976). Attempts microcephaly, midface hypoplasia, congenital aural atresia (CAA), geni- to identify critical regions remain inconclusive. Hence, aneusomies of tourinary malformations, myelination disorders, hypotonia and mental chromosome 18 and the determination of genotype/phenotype correla- retardation (MR) (Cody et al., 1999; De Grouchy et al., 1964; Strathdee tions are of great clinical relevance. The advent of oligonucleotide array et al., 1995; Wertelecki and Gerald, 1971). Proximal interstitial deletions comparative genomic hybridization (array CGH) has enhanced the field involving bands q12 to q21 have been less frequently described (Harris of chromosomal aberration detection. Using array CGH coupled with et al., 1975; Krasikov et al., 1992; Schinzel et al., 1991). Furthermore, par- conventional genetic techniques, we identified and described for the tial duplications of chromosome 18 have been intensively analyzed by first time a case of combined interstitial duplication 18q22.1, triplication 18q22.1q22.2 and terminal deletion 18q22.2q23 presenting with leukencephalopathy, aural atresia, microcephaly, short stature and men- Abbreviations: 18q deletion syndrome, 18q− syndrome; Array CGH, array compara- tal retardation. tive genomic hybridization; CNS, central nervous system; CAA, congenital aural atresia; FISH, fluorescence in situ hybridization; UCSC, genome browser hosted by the University of California, Santa Cruz; GH, growth hormone; Kaufman Assessment Battery for children, 2. Material and methods K-ABC test; MRI, magnetic resonance imaging; MR, mental retardation; MBP, myelin basic protein gene; NCBI, National Center for Biotechnology Information; OMIM, Online 2.1. Karyotype Mendelian Inheritance in Man. ⁎ Corresponding author at: Department of Pediatric Neurology, Charité-Universitätsmedizin For chromosome analysis peripheral blood lymphocytes from the Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. Tel./fax: +49 30 450 566112x920. index patient and his parents were karyotyped using standard proto- E-mail address: [email protected] (A.M. Kaindl). cols for cultivation and GTG banding.

2.2. Array CGH analysis head circumference 1 cm below 3rd centile) and generalized muscular hypotonia. A unilateral narrow auditory canal and a conductive hearing We obtained blood samples from the index patient and his parents after loss were noted. Endocrinological examinations revealed normal growth written informed consent. Genomic DNA was isolated from peripheral hormone and thyroid function. At this age, magnetic resonance imaging blood lymphocytes according to standard procedures. Patient and female (MRI) of the brain and spine illustrated a marked leukencephalopathy reference DNA (Promega, Mannheim, Germany) were labeled with Cy3 with no myelinisation in the T2 sequence and a dilatation of the external and Cy5 using the Genomic DNA Enzymatic Labeling Kit (Agilent, Santa and internal subarachnoid space (Fig. 1C). Hence, metabolic tests were Clara, USA) and mixed according to the manufacturer's protocol. The mix- conducted but showed only a mild increase of lactate and pyruvate ture was hybridized on a Microarray Kit 244A (Agilent) and incubated for with a normal lactate/pyruvate ratio and normal results for amino acids, 48 h in a hybridization oven. The chip contains 236,000 60-mer oligonu- organic acids, oligosaccharides, glycosaminoglycanes and acylcarnitines. cleotides plus controls resulting in an average resolution of 8.9 kb. Abdominal organ malformations could be excluded by abdominal ultra- After scanning the chip on the Agilent Microarray Scanner, the sound. There was no evidence of cardiac disease. In the following years, data was processed with the Feature Extraction software and ana- the boy repeatedly presented to our hospital with only partly infection- lyzed with the Agilent Genomic Workbench version 6.5. DNA of associated emesis and ketoacidosis. Neurological examination including the parents was tested with the father's DNA as patient and the Munich functional development screening revealed a global retardation mother's DNA as reference DNA. with a delay in developmental milestones: He sat independently at For the validation of the array-CGH results, the Cytochip ISCA 180K 10 months of age, started walking independently at the age of 18 months (BlueGnome, Cambridge, UK) was used as a second array platform. This and spoke first words at the age of two years. His cognitive ability was chip contains 180,000 probes with an average spacing of 25 kb in dis- measured with the K-ABC test (Kaufman Assessment Battery for chil- ease regions and up to 100 kb in the backbone region. Patient and ref- dren) at the age of 4 and 5; 9 years and showed mild underperforming erence DNA were labeled with the Cytochip Oligo dUTP labeling kit with pronounced deficiency of the acoustic memory, fine motor skills (BlueGnome) and hybridized according to the manufacturer's protocol. and concentration (mental processing composite 80, sequential process- Data was analyzed with the BlueFuse Multi software version 2.6 ing scales 71, simultaneous processing scales 88 and achievement scales (BlueGnome). Interpretation of the results was based on the Ensembl 75; normal scales 85– 115). The developmental test of visual perception genome browser (human genome build GRCh37/hg19). 2 performed at the age of 7 years revealed results below average. At the age of 11 years, the boy is attending third grade in an integrated school. 2.3. Fluorescence in situ hybridization (FISH) His language development has been good, he can count up to 100, but he still has marked difficulties with writing and reading and Cultured blood lymphocytes from the patient and his parents were lacks any sense of time. harvested according to standard protocol to produce metaphase chro- mosomes. FISH analysis of the parents was performed on metaphase 3.2. Genetic results plates with whole chromosome painting probes for chromosome 18 (MetaSystems, Altlusheim, Germany) as well as subtelomeric probes The result of a chromosome analysis of the index patient was normal. for 18p and 18q (Abbott, Wiesbaden, Germany). Signals were analyzed Array CGH analysis revealed a de novo triple imbalance of 18q: (i) an in- using the ISIS software tool (MetaSystems, Altlusheim, Germany) (on- terstitial duplication of 827.42 bp in the 18q22.1 region, (ii) a triplication line Supplementary Fig. 1). of 1.54 Mb in the region 18q22.1q22.2 and (iii) a deletion of 9.92 Mb in the 18q22.2q23 region. His karyotype was arr 18q22.1(65,727,264– 2.4. Database search 66,554,628)×3 de novo, 18q22.1q22.2(66,554,687–68,093,381)×4 de novo and 18q22.2q23(68,093,837–78,010,032)×1 de novo (GRCh37/ Literature search was performed to identify and review critical inter- hg19) (Fig. 2, Table 1). The duplicated region contains one and parts vals for Edwards and deletion 18q syndrome using the databases of of a further gene (thioredoxin-related transmembrane protein 3, coiled- the National Center for Biotechnology Information (NCBI), the Online coil domain containing 102B), both not listed in the Online Mendelian In- Mendelian Inheritance in Man (OMIM), the genome browser hosted heritance in Man (OMIM). The triplicated region contains four genes that by the University of California, Santa Cruz (UCSC) and the Charité Uni- are listed in OMIM (docking protein 6, CD226, rotatin and suppres- versity hospital library (search terms: Edwards syndrome, duplication sor of cytokine signaling 4), and a part of the partially duplicated chromosome 18, deletion chromosome 18, 18q−, 18q22, microcepha- gene coiled-coil domain containing 102B. The deleted region con- ly, mental retardation and leukencephalopathy). tains 25 known genes of which 14 are listed in OMIM. This genetic result was confirmed by a second array CGH. 3. Results 4. Discussion 3.1. Phenotype Here we describe a first case of a combined interstitial duplication The index patient is the first of two children of non-consanguineous, of 18q22.1 (0.82 Mb), triplication of 18q22.1q22.2 (1.54 Mb) and ter- healthy German parents. His younger brother is healthy and family his- minal deletion of 18q22.2q23 (9.92 Mb) (Figs. 1 and 2). Cytogenetic tory was unremarkable with respect to neurologic disorders. The patient results were attained by array CGH analysis and confirmed by a sec- was born at term without complications after an uneventful pregnancy: ond assay (BlueGnome) (Fig. 2). Further FISH analysis revealed nor- birth weight 2580 g (15th centile), length 48 cm (3rd centile) and mal genotypes in the parents as evidence for a de novo occurrence head circumference 33 cm (10th centile). Dysmorphic features in- of chromosomal aberrations in the index patient. cluding hypertelorism, epicanthus, broad nasal bridge, secondary mi- Deletions and duplications of chromosome 18 rank among the most crocephaly, kyphosis of the thoracic spine with enhanced gap of the common autosomal anomalies with abnormalities of chromosome 18q pedicles of vertebral arches, epispadias, talipes equinovarus and prom- being the most frequent and deletions of 18q being reported in 1/40,000 inent length of both thumbs in relation to generally long, tapering fin- live births (Cody et al., 1999). Partial and complete duplications of chro- gers and toes were noted (Fig. 1A, B, online Supplementary Fig. 2). His mosome 18 are described to be as frequent as 1/3600–1/10,000 (Cereda parents retrospectively remarked on feeding difficulties with poor and Carey, 2012). The chromosomal breakpoint identified in our patient suck. At the age of ten months, the infant presented with failure to lies within a fragility site on chromosome 18, which has been described thrive (height 12 cm below 3rd centile, weight 3 kg below 3rd centile, by Debacker et al. (2007) but not by other authors (Feenstra et al., 2007; 94 S. Nguyen-Minh et al. / Gene 523 (2013) 92–98

Fig. 1. Clinical and radiological phenotype of patient. (A) Synopsis of the patient's phenotype. (B) X-ray of the left foot at age 7 demonstrating talipes. (C) Axial T2 cerebral MRI demonstrates leukoencephalopathy and dilatation of the external and internal cerebrospinal ﬂuid spaces at the age of 10 months. The axial T1 at the age of 10 months does not reveal dysmyelination.

Fig. 2. Genes located within the duplication 18q22.1 (0.82 MB), the triplication 18q22.1q22.2 (1.54 Mb) and the deletion 18q22.2q23 (9.92 Mb). (A) Array CGH results using

Agilent's Microarray Kit 244A and BlueGnome's CytoChip Oligo ISCA 180K. (B) Array CGH results with a proximal duplication 18q22.1 (log2 = 0.58) followed by a triplication

18q22.1q22.2 (log2 = 1) and a terminal deletion 18q22.2q23 (log2 = −1). Genes localized within the (C) duplicated (D) triplicated and (E) deleted region are depicted in our index patient according to UCSC genome browser on human GRCh39/hg19 including OMIM numbers. See Tables 1–3 for abbreviations. S. Nguyen-Minh et al. / Gene 523 (2013) 92–98 95 96 S. Nguyen-Minh et al. / Gene 523 (2013) 92–98

Table 1 Table 3 List of genes within duplication 18q22.1. List of genes within deletion 18q22.2q23.

Gene Protein OMIM Function Gene Protein OMIM Function

TMX3 Thioredoxin-related – Catalyzes the formation of CBLN2 Precerebellin 2 MIM*600433 Modulators in the cerebellum transmembrane protein 3 disulfide bonds and in the endocrine system CCDC102B Coiled-coil domain – Involved in subcellular NETO1 Neuropillin- and MIM*607973 Possible role as endocytic cell containing 102B infrastructure maintenance tolloid-like 1 surface receptors FBXO15 F-box only protein 15 MIM*609093 Interacts with a transcription factor essential for self-renewal of embryonic stem cells CYB5A Cytochrome b5, type MIM*613218 Converts ferric cytochrome b5 Table 2 A to ferrous cytochrome b5 List of genes within triplication 18q22.1q22.2. PEPA Peptidase A MIM*169800 Hydrolyses di- and tripeptides CNDP1 Carnosine MIM*609064 Degrades carnosine, Gene Protein OMIM Function dipeptidase 1 homocarnosine and other CCDC102B Coiled-coil – Involved in subcellular infrastructure related peptides domain maintenance ZNF236 Zinc finger protein MIM*604760 Involved in the regulation of containing 236 glucose metabolism 102B MBP Myelin basic protein MIM*159430 Essential for the compaction of DOK6 Docking MIM*611402 Intracellular adaptor in the RET myelin in mice protein 6 (rearranged during transfection) GALR1 Galanin receptor 1 MIM*600377 Neuromodulator in the brain, signaling cascade gastrointestinal system and CD226 CD226 antigen MIM*605397 Important for T cell- and natural hypothalamo pituitary axis killer cell-mediated lysis of tumor (stimulates growth hormone cells secretion) RTTN Rotatin MIM*610436 Required for left–right specification, SALL3 Sal-like 3 MIM*605079 Important developmental axial rotation and notochord regulator, essential role in development kidney development SOCS4 Suppressor of MIM*605118 Members of the cytokine-inducible NFATC1 Nuclear factor of MIM*600489 Regulates inducible expression cytokine SH2 protein (CIS) family activated T cells of different cytokine genes signaling 4 CTDP1 C-terminal domain of MIM*604927 Essential for RNA polymerase RNA polymerase II II-mediated transcription of subunit A many protein-encoding genes KCNG2 Potassium channel, MIM*605696 May contribute to cardiac voltage-gated, sub- action potential repolarization Heard et al., 2009; Strathdee et al., 1995). A combined deletion and family G, member 2 PARDD6G Partitioning-defective MIM*608976 Links small guanidine duplication/triplication of 18q is rare and can be found in only 6% of pa- protein 6 triphosphatases to atypical tients with 18q deletions (Heard et al., 2009), while simple interstitial protein kinase C deletions and simple terminal deletions occur in 15% and 69% of patients with 18q deletions, respectively. A triplication of 18q has only been described once before (Giorda et al., 2011).

4.1. Deletion 18q22.2-q23 and the deletion 18q phenotype on T2-weighted images, has been ascribed to haploinsufficiency of the The terminal deletion 18q22.2q23 in our patient does not include myelin basic protein gene (MBP), the second most abundant CNS mye- previously suggested haplolethal genes (Heard et al., 2009). In con- lin protein involved in the compaction of central nervous system myelin trast to rare interstitial deletions, more than 300 patients with ter- (Gay et al., 1997; Linnankivi et al., 2006; Miller et al., 1990; Ono et al., minal deletions of 18q have been described with a varying degree 1994; Vogel et al., 1990; Weiss et al., 1991). Our report of a deletion of of cognitive impairment, hypotonia, short stature, ear canal abnor- the MBP gene associated with dysmyelination supports this hypothesis. malities, abnormal genitalia, limb deformities (long, tapered fingers, Likewise a dysmyelination has been described in association with an proximally placed thumbs, talipes equinovarus, vertical talus, pes MBP gene deletion in mice (Griffiths, 1996; Roch et al., 1986). Finally, planus or cavus and overriding toes) and delayed myelination, a pheno- a microcephaly may be associated with 18q− syndrome and critical type summarized as the deletion 18q syndrome (18q− syndrome) regions for its appearance have been defined on 18q21.2–18q21.3 (Cody et al., 1999; Feenstra et al., 2007; Linnankivi et al., 2006; (Kline et al., 1993) or 18q21.33 (Feenstra et al., 2007). Our report Strathdee et al., 1995; Wertelecki and Gerald, 1971). On the basis of a patient with microcephaly and interstitial deletion 18q22.2q23 of these reports, candidate regions for specific features of the syn- without deletion of 18q21 may compromise the suggested critical drome have been suggested (Fig. 3). Within the candidate region region for microcephaly. 18q22.3-q23 these phenotypic features have been linked to specific genes: aural atresia is caused by mutations in TSHZ1 (Core et al., 4.2. Duplication 18q22.1/triplication 18q22.1q22.2 2007; Feenstra et al., 2011), dysmyelination and short stature are associated with ZNF516, LOC 284276, ZNF236, MBP and GALR1 and the The interstitial duplication 18q22.1 and triplication 18q22.1q22.2 in region for kidney malformation additionally comprised ZADH2, TSHZ1, our patient have not been described so far. The location of the duplica- C19orf62, CYB5A, C18orf51, CNDP1, LOC400657 and ZNF407 (Cody et al., tion proximal to the triplication in our patient is in line with previous 2009). Our patient presents with a deletion 18q22.2q23 corresponding reports of intrachromosomal triplications and supports the theory of a with the above described candidate region and the typical phenotypic common mechanism in the genesis of interstitial intrachromosomal anomalies dysmyelination, short stature and aural atresia of 18q− triplications (Giorda et al., 2011). The duplication/triplication in our pa- syndrome but absence of a kidney malformation. The absence of tient furthermore corresponds to a proposed critical region on chromo- the latter feature may be explained by its incomplete penetrance of some 18q for appearance of the Edwards syndrome phenotype (Fig. 3) 25% compared to a high penetrance of the other features of 78–100% (Turleau and de Grouchy, 1977). Still, this duplication did not induce (Cody et al., 2009). The dysmyelination in 18q− syndrome, character- the characteristic phenotype with distinct craniofacial dysmorphism, istically associated with poor differentiation of gray and white matter clenched hands and overlapping digits and internal organ malformations S. Nguyen-Minh et al. / Gene 523 (2013) 92–98 97

Fig. 3. Scheme of candidate regions for Edwards syndrome and 18q− syndrome as published by previous authors in comparison to our index patient. Positions of duplication are marked , positions of triplication are marked and positions of deletion are marked . GH = growth hormone and CAA = congenital aural atresia. * = within this region spe- ciﬁc genes were associated with speciﬁc phenotypes: (I) dysmyelination and short stature (ZNF516, LOC 284276, ZNF236, MBP and GALR1), (II) aural atresia (additionally comprehending ZADH2, TSHZ1 and C19orf62) and (III) kidney malformation (enclosing all the former genes and CYB5A, C18orf51, CNDP1, LOC400657 and ZNF407)(Cody et al., 2009).

in our patient. Our findings and few further case reports suggest that a Acknowledgments distal or terminal duplication of chromosome 18q is not sufficient for the appearance of the Edwards syndrome phenotype (Isidor et al., The authors thank the patient and his family for participating in this 2008; Quiroga et al., 2011), but that in fact a combined duplication study and acknowledge Theodor Michael, Christoph Hübner, Angelika of a specific proximal and distal region of 18q is necessary to induce Zwirner, Björn Picker and Luitgard Graul-Neumann for their discussions this phenotype. These regions may comply with a combination of and technical assistance. Our research was supported by the German 18q11 and 18q22-qter (Turleau and de Grouchy, 1977) or combination Research Foundation (DFG; SFB 665), the Sonnenfeld Stiftung and the of 18q12.1–q21.2 and 18q22.3-qter (Boghosian-Sell et al., 1994). In Berliner Krebsgesellschaft e.V. total, approximately 10 patients with Edwards syndrome phenotype among 50 patients with a partial duplication of chromosome 18 have been identified and helped to delineate further candidate regions for References this phenotype: (i) 18q21 (Matsuoka et al., 1981), (ii) CRES is proximal Binkert, F., Stranzinger, J., Schinzel, A., 1990. Partial trisomy of chromosome 18 (pter — q12) to 18q12.2 (Mucke et al., 1982) and (iii) 18q11–q12 (Fryns et al., 1978). following a familial 18;21 translocation rcp(18;21)(q12;q11). Hum. Hered. 40, 81–84. The possibility of an inconstant Edwards syndrome phenotype in our Boghosian-Sell, L., et al., 1994. Molecular mapping of the Edwards syndrome phenotype to two noncontiguous regions on chromosome 18. Am. J. Hum. Genet. 55, 476–483. index case as a consequence of incomplete penetrance and phenotype Cereda, A., Carey, J.C., 2012. The trisomy 18 syndrome. Orphanet J. Rare Dis. 7, 81. variability needs to be considered. Cody, J.D., et al., 1999. Congenital anomalies and anthropometry of 42 individuals with In conclusion, we describe a patient with a combined interstitial du- deletions of chromosome 18q. Am. J. Med. Genet. 85, 455–462. Cody, J.D., et al., 2009. Narrowing critical regions and determining penetrance for se- plication 18q22.1, triplication 18q22.1q22.2 and deletion 18q22.2q23 lected 18q− phenotypes. Am. J. Med. Genet. A 149A, 1421–1430. with phenotypic traits of 18q deletion syndrome without overt clinical Core, N., Caubit, X., Metchat, A., Boned, A., Djabali, M., Fasano, L., 2007. Tshz1 is required signs of Edwards syndrome. The duplication/deletion identified in for axial skeleton, soft palate and middle ear development in mice. Dev. Biol. 308, 407–420. the index patient lies within a previously suggested fragile site on De Grouchy, J., Royer, P., Salmon, C., Lamy, M., 1964. Partial deletion of the long arms of chromosome 18 (Debacker et al., 2007) and does not contain pro- the chromosome 18. Pathol. Biol. (Paris) 12, 579–582. posed haplolethal genes (Heard et al., 2009). This report supports Debacker, K., et al., 2007. FRA18C: a new aphidicolin-inducible fragile site on chromo- the hypothesis of MBP haploinsufficiency in dysmyelination and allows some 18q22, possibly associated with in vivo chromosome breakage. J. Med. Genet. 44, 347–352. for reevaluation of the critical region for appearance of microcephaly Feenstra, I., et al., 2007. Genotype–phenotype mapping of chromosome 18q deletions by in 18q− syndrome. Even though various authors have attempted to high-resolution array CGH: an update of the phenotypic map. Am. J. Med. Genet. A – clarify genotype–phenotype correlations of chromosome 18 for several 143A, 1858 1867. Feenstra, I., et al., 2011. Disruption of teashirt zinc finger homeobox 1 is associated with decades, the candidate regions for distinct phenotypes remain to congenital aural atresia in humans. Am. J. Hum. Genet. 89, 813–819. be identified in order to improve patient consultation and potentially Fryns, J.P., Detavernier, F., van Fleteren, A., van den Berghe, H., 1978. Partial trisomy allow for therapeutic consequences for affected patients. 18q in a newborn with typical 18 trisomy phenotype. Hum. Genet. 44, 201–205. Gay, C.T., et al., 1997. Magnetic resonance imaging demonstrates incomplete myelination Supplementary data to this article can be found online at http:// in 18q− syndrome: evidence for myelin basic protein haploinsufficiency. Am. J. Med. dx.doi.org/10.1016/j.gene.2013.03.078. Genet. 74, 422–431. 98 S. Nguyen-Minh et al. / Gene 523 (2013) 92–98

Giorda, R., et al., 2011. Common structural features characterize interstitial intrachro- Neu, R.L., et al., 1976. Inclusion of satellites in an 18/21 translocation chromosome mosomal Xp and 18q triplications. Am. J. Med. Genet. A 155A, 2681–2687. shown by ammonical-silver staining (sat-banding) in case of partial trisomy 18. Griffiths, I.R., 1996. Myelin mutants: model systems for the study of normal and abnor- J. Med. Genet. 13, 520–522. mal myelination. Bioessays 18, 789–797. Ono, J., Harada, K., Yamamoto, T., Onoe, S., Okada, S., 1994. Delayed myelination in a pa- Harris, L.S., Kahanowicz, Y., Shimmyo, M., 1975. Corneal anesthesia induced by soaps tient with 18q− syndrome. Pediatr. Neurol. 11, 64–67. and surfactants, lack of correlation in rabbits and humans. Ophthalmologica 170, Quiroga, R., et al., 2011. Partial duplication of 18q including a distal critical region for 320–325. Edwards syndrome in a patient with normal phenotype and oligoasthenospermia: Heard, P.L., Carter, E.M., Crandall, A.C., Sebold, C., Hale, D.E., Cody, J.D., 2009. High resolu- case report. Cytogenet. Genome Res. 133, 78–83. tion genomic analysis of 18q− using oligo-microarray comparative genomic hybrid- Roch, J.M., Brown-Luedi, M., Cooper, B.J., Matthieu, J.M., 1986. Mice heterozygous for ization (aCGH). Am. J. Med. Genet. A 149A, 1431–1437. the mld mutation have intermediate levels of myelin basic protein mRNA and its Isidor, B., et al., 2008. Inherited 18q23 duplication in a fetus with multiple congenital translation products. Brain Res. 387, 137–144. anomalies. Eur. J. Med. Genet. 51, 231–238. Schinzel, A., et al., 1991. Interstitial deletion of the long arm of chromosome 18, Kline, A.D., et al., 1993. Molecular analysis of the 18q− syndrome and correlation with del(18)(q12.2q21.1): a report of three cases of an autosomal deletion with a mild phenotype. Am. J. Hum. Genet. 52, 895–906. phenotype. J. Med. Genet. 28, 352–355. Krasikov, N., Thompson, K., Sekhon, G.S., 1992. Monosomy 18q12.1–21.1: a recogniz- Strathdee, G., Zackai, E.H., Shapiro, R., Kamholz, J., Overhauser, J., 1995. Analysis of able aneuploidy syndrome? Report of a patient and review of the literature. Am. clinical variation seen in patients with 18q terminal deletions. Am. J. Med. Genet. J. Med. Genet. 43, 531–534. 59, 476–483. Linnankivi, T., et al., 2006. 18q deletions: clinical, molecular, and brain MRI findings of Turleau, C., de Grouchy, J., 1977. Trisomy 18qter and trisomy mapping of chromosome 14 individuals. Am. J. Med. Genet. A 140, 331–339. 18. Clin. Genet. 12, 361–371. Matsuoka, R., Matsuyama, S., Yamamoto, Y., Kuroki, Y., Matsui, I., 1981. Trisomy 18q. A Vogel,H.,Urich,H.,Horoupian,D.S.,Wertelecki,W.,1990.Thebraininthe18q− case report and review of karyotype–phenotype correlations. Hum. Genet. 57, 78–82. syndrome.Dev.Med.ChildNeurol.32,732–737. Miller, G., Mowrey, P.N., Hopper, K.D., Frankel, C.A., Ladda, R.L., 1990. Neurologic man- Weiss, B.J., et al., 1991. Segmental spinal muscular atrophy and dermatological findings ifestations in 18q− syndrome. Am. J. Med. Genet. 37, 128–132. in a patient with chromosome 18q deletion. Ann. Neurol. 30, 419–423. Mucke, J., Trautmann, U., Sandig, K.R., Theile, H., 1982. The crucial band for phenotype Wertelecki, W., Gerald, P.S., 1971. Clinical and chromosomal studies of the 18q− of trisomy 18. Hum. Genet. 60, 205. syndrome.J.Pediatr.78,44–52. 本文献由“学霸图书馆-文献云下载”收集自网络，仅供学习交流使用。

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