- Email: [email protected]
A de novo 8q22.2-24.3 duplication in a patient with mild phenotype
European Journal of Medical Genetics 55 (2012) 67e70
Contents lists available at SciVerse ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Short report
A de novo 8q22.2-24.3 duplication in a patient with mild phenotype D. Concolino a, *, M.A. Iembo a, M.T. Moricca a, M. Rapsomaniki a, R. Marotta b, O. Galesi c, M. Fichera c, C. Romano d, P. Strisciuglio a,1 a
Department of Pediatrics, University “Magna Graecia”, Catanzaro, Italy Department of Psychiatry, University “Magna Graecia”, Catanzaro, Italy c Laboratory of Genetic Diagnosis, I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy d Unit of Pediatrics and Medical Genetics, I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 February 2011 Accepted 10 September 2011 Available online 25 September 2011
We report a new case of 8q interstitial duplication in a patient with dysmorphic features, umbilical hernia, cryptorchidism, short stature, congenital heart defect and mild mental retardation (MR). Chromosome analysis with high resolution QFQ bands showed 46,XY, 8qþ, which was interpreted as a partial duplication of the distal long arm of chromosome 8 (q22 / qter). This chromosomal aberration was further characterized using fluorescence in situ hybridization (FISH) analyses with multiple DNA probes and array-CGH (Comparative Genomic Hybridization) experiment which demonstrated a de novo direct duplication (8)(q22.2-q24.3). We have compared this case with other partially trisomic 8q patients reported in literature and highlighted the common clinical features in 8q22-8q24 duplication syndrome. Published by Elsevier Masson SAS.
Keywords: 8q22.2 / 8q24.3 Partial duplication 8q
1. Introduction
2. Case report
Several patients with duplications of the long arm of chromosome 8 have been reported and associated clinical signs are variable and correlate with the size of duplicated segment. Patients with duplications 8q22-qter have a broad clinical spectrum. The common manifestations include short stature, dysmorphic signs cryptorchidism, hypertrichosis, congenital heart malformations and MR with frequent occurrence of seizures [1]. The typical facial features include broad face, downslanting palpebral fissures, hypertelorism, depressed bridge, anteverted tip of the nose, long philtrum, micrognathia and large ears [1]. The pure interstitial 8q duplications are rare events with few cases reported in the literature, most of them, only characterized by karyotyping and/or FISH. Indeed to our knowledge only one8q23-q24 duplication has been studied by array-CGH [2]. We report a new case of de novo interstitial duplication 8q22.2-q24.3 in a child with short stature, facial dysmorphisms and heart malformations with mild MR. The literature of dup(8)(q22-qter) was reviewed and the phenotypic features of our patient were compared with the previously reported cases.
The propositus is the second child of healthy and unrelated parents; the family history, the pregnancy and the delivery were unremarkable. APGAR score was 10 at one and five minutes. He was born at 40 weeks of gestation with a weight of 2850 g (10e25th centile), a length of 49 cm (25th centile) and head circumference of 35.5 cm (75th centile). At birth he was found to have dysmorphic signs as flat occiput, hypertelorism and microretrognathia, bilateral cryptorchidism, atrial and ventricular septal defects. At 6 months of age he had a surgical correction of interventricular defect. Physical examination at age of 7 months showed a weight of 5400 g (<5th centile), a length of 65 cm (<5th centile), head circumference of 43.5 cm (25th centile). Facial dysmorphic signs (Fig. 1a) include flat occiput, prominent forehead, glabellar fistula, large nasal bridge with anteverted nares, micrognathia, posteriorly rotated ears, hypertelorism, thin lips, long philtrum, high palate. He had clinodactyly, hypoplasia of distal phalanges, syndactyly of 2nd and 3rd toes, umbilical hernia, bilateral cryptorchidism. The ophthalmologic evaluation showed a megalocornea (>12 mm), while the visual-evoked potentials and elettroretinogram were normal. Routine laboratory analysis as plasma transaminases (AST, ALT), gamma glutamyltranspeptidase (g-GT), CPK, TSH, T3, T4, abdominal sonography and electroencephalogram were normal. Frontal bone and cerebral MRI scans at 22 months of age indicated a little frontal meningocele that was removed surgically (Fig. 1b). At 24 months of age he had a surgical correction of undescended testes.
* Correspondence author. Department of Pediatrics University “Magna Graecia” of Catanzaro, c/o Ospedale Civile A. Pugliese, Viale Pio X, 88100 Catanzaro, Italy. Tel.: þ39 0961 883462; fax: þ39 0961 883489. E-mail address: [email protected] (D. Concolino). 1 Present address: Department of Pediatrics, University “Federico II”, Naples, Italy. 1769-7212/$ e see front matter Published by Elsevier Masson SAS. doi:10.1016/j.ejmg.2011.09.001
68
D. Concolino et al. / European Journal of Medical Genetics 55 (2012) 67e70
Fig. 1. Facial appearance of the patient at the age of: 7 months (a) and 26 months (b). Note prominent forehead, glabellar fistula, large nasal bridge with anteverted nares, micrognathia, hypertelorism, thin lips, long philtrum.
The neurological examination and the evaluation of psychomotor development with the Brunet-Lézine scale at the age of 12 months, 2 years and 3 years (DQ 98), were in the normal range. No other malformations were present. At the age of 6 years of age a new ophthalmologic evaluation showed a keratoconus. The patient was subsequently followed by annual neuropsychiatric evaluation based on clinical interview, behaviour observation and administration of mental tests. At 7 years of age, the assessment of intellective development, with the administration of WISC-R intelligence test, revealed a mild mental retardation. Global I.Q. was 56 points, Verbal I.Q. was 57 points while Performance I.Q. was below 58 points. The child showed indecision and absence of original strategies in the setting of the answer; nevertheless, he strove to achieve the requested items, with poor outcome. There was attention deficiency heavily influencing the performances during WISC-R administration. Neuropsychological area was particularly immature. There weren’t thought and senso-perceptive disturbances. Affectivity was not much mature, mood tone was prone to dysthymia. Available data show a slow and harmonic evolutive process, globally satisfactory during the first years of observation, with subsequent progressive slowing of development. The patient has never developed epilepsy.
Microarray chip was scanned by the Agilent Microarray Scanner (G2565BA) and data analysis was performed using Agilent Feature Extraction Software v 10.7 and DNA Analytics software v 4.0 (Agilent Technologies). 3.2. Results Proband’s karyotype showed 46 chromosomes with a longer 8q chromosome (Fig. 2). Parents’ karyotype was normal. Wcp with libraries of all chromosomes revealed that the abnormal chromosome 8 was entirely composed by chromosome 8 material. The subtelomeric probes specific for chromosome 8 showed normal signals in both telomeres, leading to the interpretation of a direct interstitial duplication FISH analysis with BAC from 8q (Supplementary file) was performed and demonstrated that the duplicated region extended from 8q22.2 (RP11-102K7 clone-101.2 Mb) to 8q24.3 (RP11-120B22 clone-144.3 Mb) (Supplementary file).
3. Cytogenetic and molecular analyses 3.1. Materials and methods Chromosome analysis was performed on propositus and parents’ blood using QFQ banded metaphase from synchronized peripheral lymphocyte cultures according to standard procedures. FISH analysis with whole chromosome painting (wcp) and with telomere-specific probes for all chromosomes was carried out on patient’s metaphases. Other FISH experiments were performed with bacterial artificial chromosome (BAC) clones containing chromosome 8q specific sequences from several locations according to the publicly available genome resources (NCBI Map Viewer: http://genome.ucsc.edu). Array-CGH was performed using a Human Genome CGH Microarray Kit 44k Custom (Agilent Technologies, Palo Alto, CA).
Fig. 2. Ideogram and cut-out of normal and abnormal chromosome 8.
D. Concolino et al. / European Journal of Medical Genetics 55 (2012) 67e70
The array-CGH analysis revealed a duplication encompassing about a 44.9 Mb chromosomal region in 8q22.2 / 8q24.3 from centromeric breakpoint 100338614e100413,534 pb to telomeric breakpoint 145339830e145464,363 pb (hg18) (Fig. 3). No other imbalances were detected in the rest of the genome. 4. Discussion Cytogenetic and molecular analysis of our patient revealed a “pure” de novo duplication of approximately 44.9 Mb affecting the 8q22.2-q24.3 chromosome without duplication of 8q subtelomeric region. Obviously, this large rearrangement encompasses many genes and some of them such as COH1, TRPS1 and EXT1 are linked to developmental diseases. Although several cases of 8q duplication have been reported, most of them either result from balanced translocations, having concomitant deletions of other chromosome segments or are otherwise associated with rearrangements elsewhere in the genome [3e9], thus impairing a genotypeephenotype correlation among these patients and those carrying the less frequently reported “pure” interstitial duplications
69
of chromosome 8q22-q24.3 [2,10e12]. Nevertheless, phenotype comparison of all these patients including our patient suggests that hypertelorism, microretrognathia, telecanthus and a variable degree of mental retardation are key clinical features associated with the 8q22.2-q24.3 duplication. A more confident genotypeephenotype correlation may be drawn between our proband and the patient with facial dysmorphism, hyperopia and mild developmental delay carrying a 8q23.2-q24.21 duplication studied by array-CGH [2]. Although a large size difference between duplications, both patients showed similar characteristic dysmorphic features, and mild to moderate MR (Table 1), suggesting that key genes involved in the common clinical features associated with the 8q22.2-q24.3 duplication are located in the 8q23.2-q24.21 chromosomal region. Interestingly, Bonaglia et al. [13] reported a de novo 2.3 Mb inverted duplication of 8q24.3 in a subject with severe psychomotor retardation and epilepsy suggesting that small subtelomeric de novo duplications may be responsible for severe mental retardation. The authors proposed the duplication of the GRINA gene (MIM 138251), a glutamate binding subunit of NMDA receptor ion channel, as the
Fig. 3. Array-CGH.
70
D. Concolino et al. / European Journal of Medical Genetics 55 (2012) 67e70
Table 1 Clinical manifestations of the patients with duplication 8q22-q24 characterized by aCGH.
Duplicated segment Facial features Hypertelorism Epicanthal folds Telecanthus Laterally hypoplastic eyebows Microretrognathia Low-set ears Protruding ears Long philtrum Eyes anomalies Visual defects Keratoconus Megalocornea Birth defects Congenital cardiac defects Cryptorchidism Frontal meningocele Bifid uvula Neurologic anomalies Hypotonia Mental retardation Hearing loss Seizures Hypertrichosis Limb anomalies Equinovarus Distal phalanges hypoplasia Syndactyly of 2nd and 3rd toes
Present case
Wheeler 2010
8q22.2-q24.2
8q23.3-q24.21
þ þ þ þ
þ þ þ þ þ þ þ
þ þ
þ
þ þ þ _
þ
þ
þ þ þ þ
þ þ
þ
molecular cause of the epilepsy in their patient. Since the GRINA gene is included in the duplication identified in our patient, we cannot exclude a development of epilepsy in his lifetime. We found no clear correlation between the size of the duplication and the level of developmental delay. For example ViannaMorgante et al. [11] reported on a patient with severe MR, carrying a similar duplication of our proband while the patient’s severe MR described by Bonaglia et al. [13] contrasts with the mild MR in three brothers carrying a familial distal trisomy 8(q24.13---qter) reported by Romain et al. [8]. Further molecular characterization of these cases may help in discerning whether other overlooked imbalances may explain phenotype differences in patients sharing apparently similar 8q duplications or this may account for
variable expressivity of the 8q duplication. In conclusion, our case may provide relevant information for genetic counselling concerning the natural history and prognosis of patients with this rare duplication. Appendix. Supplementary material Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ejmg.2011.09.001. References [1] A. Schinzel, Catalogue of Unbalanced Chromosome Aberration in Man, second rev ed. Walter de Gruyter, Berlin, 2001, pp. 360e362. [2] P.G. Wheeler, 8q23-q24 duplication-Further delineation of a rare chromosomal abnormality, Am. J. Med. Genet. 152A (2010) 459e463. [3] M.A. Ergun, S. Balci, E. Konac, D. Kan, S. Menevse, O. Bartsch, Trisomy of 8q22.3 approximately q23-qter following an unbalanced 1;8 translocation in a boy with multiple anomalies, Turk. J. Pediatr. 46 (2004) 384e387. [4] A.P. Walker, M. Bocian, Partial duplication 8q12——q21.2 in two sibs with maternally derived insertional and reciprocal translocations: case reports and review of partial duplications of chromosome 8, Am. J. Med. Genet. 27 (1987) 3e22. [5] S. Puvabanditsin, E. Garrow, F.A. Rabi, R. Titapiwatanakun, K.M. Kuniyoshi, Partial trisomy 8q and partial monosomy 18p: a case report, Ann. Genet. 47 (2004) 399e403. [6] K. Wakui, H. Ohashi, A. Yamagishi, S. Hamano, T. Nara, S. Ishikiriyama, Y. Nakamura, Y. Fukushima, Interstitial duplication 8q22-q24: report of a case proven by FISH with mapped cosmid probes, Am. J. Med. Genet. 65 (1996) 36e39. [7] M. Sasiadek, A. Stembalska, K. Schlade, M. Zych, 8q22–>qter duplication in a child with multiple congenital malformations: case report, Med. Sci. Monit. 6 (2000) 141e144. [8] D.R. Romain, R.A. Bloxham, L.M. Columbano-Green, C.J. Chapman, R.G. Parfitt, R.H. Smythe, H. Cairney, Familial distal trisomy 8(q24.13——qter), J. Med. Genet. 26 (1989) 133e138. [9] S. Stengel-Rutkowski, K. Lohse, C. Herzog, C. Apacik, J. Couturier, A. Albert, B. Belohradsky, Partial trisomy 8q. Two case reports with maternal translocation and inverted insertion: phenotype analyses and reflections on the risk, Clin. Genet. 42 (1992) 178e185. [10] Y.S. Fan, V.M. Siu, Molecular cytogenetic characterization of a derivative chromosome 8 with an inverted duplication of 8p21.3–>p23.3 and a rearranged duplication of 8q24.13–>qter, Am. J. Med. Genet. 102 (2001) 266e271. [11] A.M. Vianna-Morgante, R.C. Mingroni-Netto, A.C.C. Barbosa, P.A. Otto, C. Rosenberg, FRAXF in a patient with chromosome 8 duplication, J. Med. Genet. 33 (1996) 611e614. [12] K. Naritomi, K. Hirayama, Partial trisomy of distal 8q derived from mother with 8q23.3-24.13 deletion, and relatively mild expression of trichorhinophalangeal syndrome I, Hum. Genet. 82 (1989) 199e201. [13] M.C. Bonaglia, R. Giorda, R. Tenconi, M. Pessina, T. Pramparo, R. Borgatti, O. Zuffardi, A 2.3 Mb duplication of chromosome 8q24.3 associated with severe mental retardation and epilepsy detected by standard karyotype, Eur. J. Hum. Genet. 13 (2005) 586e591.
Contents lists available at SciVerse ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Short report
A de novo 8q22.2-24.3 duplication in a patient with mild phenotype D. Concolino a, *, M.A. Iembo a, M.T. Moricca a, M. Rapsomaniki a, R. Marotta b, O. Galesi c, M. Fichera c, C. Romano d, P. Strisciuglio a,1 a
Department of Pediatrics, University “Magna Graecia”, Catanzaro, Italy Department of Psychiatry, University “Magna Graecia”, Catanzaro, Italy c Laboratory of Genetic Diagnosis, I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy d Unit of Pediatrics and Medical Genetics, I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 February 2011 Accepted 10 September 2011 Available online 25 September 2011
We report a new case of 8q interstitial duplication in a patient with dysmorphic features, umbilical hernia, cryptorchidism, short stature, congenital heart defect and mild mental retardation (MR). Chromosome analysis with high resolution QFQ bands showed 46,XY, 8qþ, which was interpreted as a partial duplication of the distal long arm of chromosome 8 (q22 / qter). This chromosomal aberration was further characterized using fluorescence in situ hybridization (FISH) analyses with multiple DNA probes and array-CGH (Comparative Genomic Hybridization) experiment which demonstrated a de novo direct duplication (8)(q22.2-q24.3). We have compared this case with other partially trisomic 8q patients reported in literature and highlighted the common clinical features in 8q22-8q24 duplication syndrome. Published by Elsevier Masson SAS.
Keywords: 8q22.2 / 8q24.3 Partial duplication 8q
1. Introduction
2. Case report
Several patients with duplications of the long arm of chromosome 8 have been reported and associated clinical signs are variable and correlate with the size of duplicated segment. Patients with duplications 8q22-qter have a broad clinical spectrum. The common manifestations include short stature, dysmorphic signs cryptorchidism, hypertrichosis, congenital heart malformations and MR with frequent occurrence of seizures [1]. The typical facial features include broad face, downslanting palpebral fissures, hypertelorism, depressed bridge, anteverted tip of the nose, long philtrum, micrognathia and large ears [1]. The pure interstitial 8q duplications are rare events with few cases reported in the literature, most of them, only characterized by karyotyping and/or FISH. Indeed to our knowledge only one8q23-q24 duplication has been studied by array-CGH [2]. We report a new case of de novo interstitial duplication 8q22.2-q24.3 in a child with short stature, facial dysmorphisms and heart malformations with mild MR. The literature of dup(8)(q22-qter) was reviewed and the phenotypic features of our patient were compared with the previously reported cases.
The propositus is the second child of healthy and unrelated parents; the family history, the pregnancy and the delivery were unremarkable. APGAR score was 10 at one and five minutes. He was born at 40 weeks of gestation with a weight of 2850 g (10e25th centile), a length of 49 cm (25th centile) and head circumference of 35.5 cm (75th centile). At birth he was found to have dysmorphic signs as flat occiput, hypertelorism and microretrognathia, bilateral cryptorchidism, atrial and ventricular septal defects. At 6 months of age he had a surgical correction of interventricular defect. Physical examination at age of 7 months showed a weight of 5400 g (<5th centile), a length of 65 cm (<5th centile), head circumference of 43.5 cm (25th centile). Facial dysmorphic signs (Fig. 1a) include flat occiput, prominent forehead, glabellar fistula, large nasal bridge with anteverted nares, micrognathia, posteriorly rotated ears, hypertelorism, thin lips, long philtrum, high palate. He had clinodactyly, hypoplasia of distal phalanges, syndactyly of 2nd and 3rd toes, umbilical hernia, bilateral cryptorchidism. The ophthalmologic evaluation showed a megalocornea (>12 mm), while the visual-evoked potentials and elettroretinogram were normal. Routine laboratory analysis as plasma transaminases (AST, ALT), gamma glutamyltranspeptidase (g-GT), CPK, TSH, T3, T4, abdominal sonography and electroencephalogram were normal. Frontal bone and cerebral MRI scans at 22 months of age indicated a little frontal meningocele that was removed surgically (Fig. 1b). At 24 months of age he had a surgical correction of undescended testes.
* Correspondence author. Department of Pediatrics University “Magna Graecia” of Catanzaro, c/o Ospedale Civile A. Pugliese, Viale Pio X, 88100 Catanzaro, Italy. Tel.: þ39 0961 883462; fax: þ39 0961 883489. E-mail address: [email protected] (D. Concolino). 1 Present address: Department of Pediatrics, University “Federico II”, Naples, Italy. 1769-7212/$ e see front matter Published by Elsevier Masson SAS. doi:10.1016/j.ejmg.2011.09.001
68
D. Concolino et al. / European Journal of Medical Genetics 55 (2012) 67e70
Fig. 1. Facial appearance of the patient at the age of: 7 months (a) and 26 months (b). Note prominent forehead, glabellar fistula, large nasal bridge with anteverted nares, micrognathia, hypertelorism, thin lips, long philtrum.
The neurological examination and the evaluation of psychomotor development with the Brunet-Lézine scale at the age of 12 months, 2 years and 3 years (DQ 98), were in the normal range. No other malformations were present. At the age of 6 years of age a new ophthalmologic evaluation showed a keratoconus. The patient was subsequently followed by annual neuropsychiatric evaluation based on clinical interview, behaviour observation and administration of mental tests. At 7 years of age, the assessment of intellective development, with the administration of WISC-R intelligence test, revealed a mild mental retardation. Global I.Q. was 56 points, Verbal I.Q. was 57 points while Performance I.Q. was below 58 points. The child showed indecision and absence of original strategies in the setting of the answer; nevertheless, he strove to achieve the requested items, with poor outcome. There was attention deficiency heavily influencing the performances during WISC-R administration. Neuropsychological area was particularly immature. There weren’t thought and senso-perceptive disturbances. Affectivity was not much mature, mood tone was prone to dysthymia. Available data show a slow and harmonic evolutive process, globally satisfactory during the first years of observation, with subsequent progressive slowing of development. The patient has never developed epilepsy.
Microarray chip was scanned by the Agilent Microarray Scanner (G2565BA) and data analysis was performed using Agilent Feature Extraction Software v 10.7 and DNA Analytics software v 4.0 (Agilent Technologies). 3.2. Results Proband’s karyotype showed 46 chromosomes with a longer 8q chromosome (Fig. 2). Parents’ karyotype was normal. Wcp with libraries of all chromosomes revealed that the abnormal chromosome 8 was entirely composed by chromosome 8 material. The subtelomeric probes specific for chromosome 8 showed normal signals in both telomeres, leading to the interpretation of a direct interstitial duplication FISH analysis with BAC from 8q (Supplementary file) was performed and demonstrated that the duplicated region extended from 8q22.2 (RP11-102K7 clone-101.2 Mb) to 8q24.3 (RP11-120B22 clone-144.3 Mb) (Supplementary file).
3. Cytogenetic and molecular analyses 3.1. Materials and methods Chromosome analysis was performed on propositus and parents’ blood using QFQ banded metaphase from synchronized peripheral lymphocyte cultures according to standard procedures. FISH analysis with whole chromosome painting (wcp) and with telomere-specific probes for all chromosomes was carried out on patient’s metaphases. Other FISH experiments were performed with bacterial artificial chromosome (BAC) clones containing chromosome 8q specific sequences from several locations according to the publicly available genome resources (NCBI Map Viewer: http://genome.ucsc.edu). Array-CGH was performed using a Human Genome CGH Microarray Kit 44k Custom (Agilent Technologies, Palo Alto, CA).
Fig. 2. Ideogram and cut-out of normal and abnormal chromosome 8.
D. Concolino et al. / European Journal of Medical Genetics 55 (2012) 67e70
The array-CGH analysis revealed a duplication encompassing about a 44.9 Mb chromosomal region in 8q22.2 / 8q24.3 from centromeric breakpoint 100338614e100413,534 pb to telomeric breakpoint 145339830e145464,363 pb (hg18) (Fig. 3). No other imbalances were detected in the rest of the genome. 4. Discussion Cytogenetic and molecular analysis of our patient revealed a “pure” de novo duplication of approximately 44.9 Mb affecting the 8q22.2-q24.3 chromosome without duplication of 8q subtelomeric region. Obviously, this large rearrangement encompasses many genes and some of them such as COH1, TRPS1 and EXT1 are linked to developmental diseases. Although several cases of 8q duplication have been reported, most of them either result from balanced translocations, having concomitant deletions of other chromosome segments or are otherwise associated with rearrangements elsewhere in the genome [3e9], thus impairing a genotypeephenotype correlation among these patients and those carrying the less frequently reported “pure” interstitial duplications
69
of chromosome 8q22-q24.3 [2,10e12]. Nevertheless, phenotype comparison of all these patients including our patient suggests that hypertelorism, microretrognathia, telecanthus and a variable degree of mental retardation are key clinical features associated with the 8q22.2-q24.3 duplication. A more confident genotypeephenotype correlation may be drawn between our proband and the patient with facial dysmorphism, hyperopia and mild developmental delay carrying a 8q23.2-q24.21 duplication studied by array-CGH [2]. Although a large size difference between duplications, both patients showed similar characteristic dysmorphic features, and mild to moderate MR (Table 1), suggesting that key genes involved in the common clinical features associated with the 8q22.2-q24.3 duplication are located in the 8q23.2-q24.21 chromosomal region. Interestingly, Bonaglia et al. [13] reported a de novo 2.3 Mb inverted duplication of 8q24.3 in a subject with severe psychomotor retardation and epilepsy suggesting that small subtelomeric de novo duplications may be responsible for severe mental retardation. The authors proposed the duplication of the GRINA gene (MIM 138251), a glutamate binding subunit of NMDA receptor ion channel, as the
Fig. 3. Array-CGH.
70
D. Concolino et al. / European Journal of Medical Genetics 55 (2012) 67e70
Table 1 Clinical manifestations of the patients with duplication 8q22-q24 characterized by aCGH.
Duplicated segment Facial features Hypertelorism Epicanthal folds Telecanthus Laterally hypoplastic eyebows Microretrognathia Low-set ears Protruding ears Long philtrum Eyes anomalies Visual defects Keratoconus Megalocornea Birth defects Congenital cardiac defects Cryptorchidism Frontal meningocele Bifid uvula Neurologic anomalies Hypotonia Mental retardation Hearing loss Seizures Hypertrichosis Limb anomalies Equinovarus Distal phalanges hypoplasia Syndactyly of 2nd and 3rd toes
Present case
Wheeler 2010
8q22.2-q24.2
8q23.3-q24.21
þ þ þ þ
þ þ þ þ þ þ þ
þ þ
þ
þ þ þ _
þ
þ
þ þ þ þ
þ þ
þ
molecular cause of the epilepsy in their patient. Since the GRINA gene is included in the duplication identified in our patient, we cannot exclude a development of epilepsy in his lifetime. We found no clear correlation between the size of the duplication and the level of developmental delay. For example ViannaMorgante et al. [11] reported on a patient with severe MR, carrying a similar duplication of our proband while the patient’s severe MR described by Bonaglia et al. [13] contrasts with the mild MR in three brothers carrying a familial distal trisomy 8(q24.13---qter) reported by Romain et al. [8]. Further molecular characterization of these cases may help in discerning whether other overlooked imbalances may explain phenotype differences in patients sharing apparently similar 8q duplications or this may account for
variable expressivity of the 8q duplication. In conclusion, our case may provide relevant information for genetic counselling concerning the natural history and prognosis of patients with this rare duplication. Appendix. Supplementary material Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ejmg.2011.09.001. References [1] A. Schinzel, Catalogue of Unbalanced Chromosome Aberration in Man, second rev ed. Walter de Gruyter, Berlin, 2001, pp. 360e362. [2] P.G. Wheeler, 8q23-q24 duplication-Further delineation of a rare chromosomal abnormality, Am. J. Med. Genet. 152A (2010) 459e463. [3] M.A. Ergun, S. Balci, E. Konac, D. Kan, S. Menevse, O. Bartsch, Trisomy of 8q22.3 approximately q23-qter following an unbalanced 1;8 translocation in a boy with multiple anomalies, Turk. J. Pediatr. 46 (2004) 384e387. [4] A.P. Walker, M. Bocian, Partial duplication 8q12——q21.2 in two sibs with maternally derived insertional and reciprocal translocations: case reports and review of partial duplications of chromosome 8, Am. J. Med. Genet. 27 (1987) 3e22. [5] S. Puvabanditsin, E. Garrow, F.A. Rabi, R. Titapiwatanakun, K.M. Kuniyoshi, Partial trisomy 8q and partial monosomy 18p: a case report, Ann. Genet. 47 (2004) 399e403. [6] K. Wakui, H. Ohashi, A. Yamagishi, S. Hamano, T. Nara, S. Ishikiriyama, Y. Nakamura, Y. Fukushima, Interstitial duplication 8q22-q24: report of a case proven by FISH with mapped cosmid probes, Am. J. Med. Genet. 65 (1996) 36e39. [7] M. Sasiadek, A. Stembalska, K. Schlade, M. Zych, 8q22–>qter duplication in a child with multiple congenital malformations: case report, Med. Sci. Monit. 6 (2000) 141e144. [8] D.R. Romain, R.A. Bloxham, L.M. Columbano-Green, C.J. Chapman, R.G. Parfitt, R.H. Smythe, H. Cairney, Familial distal trisomy 8(q24.13——qter), J. Med. Genet. 26 (1989) 133e138. [9] S. Stengel-Rutkowski, K. Lohse, C. Herzog, C. Apacik, J. Couturier, A. Albert, B. Belohradsky, Partial trisomy 8q. Two case reports with maternal translocation and inverted insertion: phenotype analyses and reflections on the risk, Clin. Genet. 42 (1992) 178e185. [10] Y.S. Fan, V.M. Siu, Molecular cytogenetic characterization of a derivative chromosome 8 with an inverted duplication of 8p21.3–>p23.3 and a rearranged duplication of 8q24.13–>qter, Am. J. Med. Genet. 102 (2001) 266e271. [11] A.M. Vianna-Morgante, R.C. Mingroni-Netto, A.C.C. Barbosa, P.A. Otto, C. Rosenberg, FRAXF in a patient with chromosome 8 duplication, J. Med. Genet. 33 (1996) 611e614. [12] K. Naritomi, K. Hirayama, Partial trisomy of distal 8q derived from mother with 8q23.3-24.13 deletion, and relatively mild expression of trichorhinophalangeal syndrome I, Hum. Genet. 82 (1989) 199e201. [13] M.C. Bonaglia, R. Giorda, R. Tenconi, M. Pessina, T. Pramparo, R. Borgatti, O. Zuffardi, A 2.3 Mb duplication of chromosome 8q24.3 associated with severe mental retardation and epilepsy detected by standard karyotype, Eur. J. Hum. Genet. 13 (2005) 586e591.