- Email: [email protected]
1.5 Mb microdeletion in 15q24 in a patient with mild OAVS phenotype
European Journal of Medical Genetics 55 (2012) 135e139
Contents lists available at SciVerse ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Chromosomal imbalance letter
1.5 Mb microdeletion in 15q24 in a patient with mild OAVS phenotype Aurore Brun a, Dorothée Cailley a, Jérôme Toutain a, Julie Bouron a, Benoit Arveiler a, b, Didier Lacombe a, b, Cyril Goizet a, b, Caroline Rooryck a, b, * a b
CHU Bordeaux, Department of Medical Genetics, Bordeaux, France Univ. Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM), EA 4576, F-33000 Bordeaux, France
a r t i c l e i n f o
a b s t r a c t
Article history: Received 8 September 2011 Accepted 20 November 2011 Available online 3 December 2011
We report on a boy presenting with features of OAVS (Oculoauriculovertebral spectrum) and carrying a 1.5 Mb microdeletion in 15q24.1q24.2. This recurrent deletion usually leads to a broad clinical spectrum but has never been found associated with features of OAVS such as ear agenesis. This observation is in accordance with OAVS being a genetically heterogeneous disorder, and points out the importance of array-CGH screening in this disorder. Ó 2011 Elsevier Masson SAS. All rights reserved.
Keywords: 15q24 microdeletion Goldenhar syndrome Oculoauriculovertebral spectrum Array-CGH Facial asymmetry Anotia Microtia
1. Introduction Oculoauriculovertebral spectrum (OAVS, OMIM 164210) is a developmental disorder involving the first and second branchial arches during embyogenesis. This spectrum includes conditions previously known as hemifacial microsomia and Goldenhar syndrome [1], and is clinically heterogeneous, ranging from isolated unilateral microtia to multiple visceral malformations. Main features are unilateral or bilateral ear anomalies (anotia, microtia, preauricular tags, and pits, ear dysplasia), hemifacial microsomia, ocular defects (coloboma of upper eyelid, epibulbar dermoids, microphthalmia), conductive and/or sensorineural hearing loss, orofacial clefts, vertebral malformations, and more rarely, cardiac, renal and cerebral malformations with possible mental retardation [2]. OAVS incidence has been estimated to 1/5,600 [3]. The majority of cases appear to be sporadic. Among the genetic forms of OAVS, familial cases are mostly in favor of a dominant autosomal transmission with incomplete penetrance and variable expressivity [4]. Chromosomal abnormalities associated with OAVS are numerous including trisomies, as well as intrachromosomal deletions and duplications, that are either inherited or de novo [5]. Epigenic pathogeny has also been suggested in the BAPX1 gene [6]. * Corresponding author. Laboratoire Maladies Rares: Génétique et Métabolisme, Université Bordeaux Segalen, Bordeaux, France. Tel.: þ33 557820357; fax: þ33 556795648. E-mail address: [email protected] (C. Rooryck). 1769-7212/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2011.11.006
However, to date, no specific gene has been involved in OAVS. Here, we describe one patient with features of OAVS, carrying a de novo deletion in 15q24.1q24.2. 2. Methods of detection 2.1. Cytogenetics Chromosome analysis was performed on peripheral blood lymphocyte cultures using conventional techniques. Chromosomes were then treated with 5-Bromodeoxyuridine, exposed to light and heat, and colored using Giemsa stains (RBG-bands). Karyotypes were established at a level of resolution of up to 550 bands per haploid set. The conventional cytogenetic analysis did not reveal any abnormality. 2.2. Array-CGH Was performed on DNA extracted from peripheral blood, using 8 60 K Oligonucleotide microarrays (Agilent Technologies Santa Clara, California). 2.3. Chromosomal anomaly Deletion occurred in chromosomal band 15q24.1q24.2 (Figs. 2 and 3), with deleted flanking probes: A_14_P131807 (centromeric)
136
A. Brun et al. / European Journal of Medical Genetics 55 (2012) 135e139
Fig. 1. Facial features of the patient at age of 24 years. A) Face view. Notice facial asymmetry and dysmorphic features typical of 15q24 deletion syndrome, including high anterior hairline, long narrow face, and broad medial eyebrows B. Profile view. Notice right ear agenesis.
and A_14_P109620 telomeric. Size of the deletion is between 1.51 and 1.62 Mb. The genomic coordinates of centromeric breakpoint are between 74,328,437 (not deleted) and 74,419,546 (deleted) and the telomeric breakpoint is between 75,931,476 (deleted) and 75,950,540 (not deleted) (Hg19).
bulbous nose, broad medial eyebrows, high anterior hairline, and long narrow face (Fig. 1). At last investigation, the patient was 24 years-old and his growth delay was persistent: weight was 40 kg (3 SD) and height was 162 cm (2.5 SD). He had myopia and strabismus. Mental retardation was mild (IQw74). He had neither vertebral nor cardiac anomalies.
2.4. Method of confirmation 4. Discussion The presence of the deletion was confirmed by FISH using probes BAC RP11-10O17 in 15q24.1 and BAC RP11-69H7 in 15q24.2 (Amplitech)(data available upon request). 2.5. Causative of the phenotype? 15q24 deletion occurred de novo, as both parents were investigated by FISH using the two same probes and no deletion was found. 3. Clinical description We describe a boy born from young and healthy non consanguineous parents (mother and father of 30 and 33 years-old respectively). He had a healthy twin sister. The pregnancy was uneventful, except for intrauterine growth retardation observed during the third trimester. In particular, there was no gestational diabetes, neither toxic exposure of the mother. He was born at 37 weeks of gestation after delivery by Caesarian section due to a transverse position. At birth, weight was 2.240 kg (2 SD), height was 48 cm (2 SD) and head circumference 33.5 cm (1.5 SD). He had hypotonia and presented two consecutive circulatory arrests, in the first weeks of life. He suffered from acute dyspnea, recurrent respiratory infections, and gastrointestinal reflux. He had moderate psychomotor delay and walked unaided at 18 months. He presented with cleft of the soft palate, right grade IV microtia and hemifacial microsomia due to malar and mandibular hypoplasia. He had bilateral conductive hearing loss (no audition on the right side due to agenesis of external auditory canal and a threshold of 50 db on the left ear) and had a hearing aid. Facial dysmorphism included
To our knowledge, our propositus is the first patient described with features of OAVS such as ear agenesis (grade IV microtia), hearing loss, hemifacial microsomia, and cleft palate, associated with a de novo deletion in 15q24.1q24.2. A recent publication describing a cohort of 86 OAVS analyzed by oligonucleotide arrayCGH, identified 12 rearrangements in different chromosomal regions, but no 15q24 deletion [5]. Our patient also presented with features usually associated with 15q24 deletion such as neonatal hypotonia, growth retardation, mental retardation, and typical facial dysmorphism (including long narrow face, broad medial eyebrows, and high anterior hairline). Table 1 summarizes clinical features of our patient compared to features of OAVS and of 15q24 deletion syndrome. Interestingly, some ear abnormalities are described in the 15q24 clinical spectrum such as ear lobe pit, cupshaped protruding ears, large or small everted ears; however unilateral grade IV microtia has never been described [7]. One additional patient has been described in the Decipher database with “low-set ears” and “external ears abnormalities”. Interestingly, our patient had a dizygotic twin. Twinning is frequently associated with OAVS condition. Several hypothesis have been enounced: the embryologic defect in OAVS could cause twinning for example via an imprinting defect causing asymmetry, or twinning could increase the risk for OAVS through abnormal vascular supply of the head (vascular disruption theory), or finally OAVS and monozygotic twinning could have a common basis due to an early malformation complex, early epigenetic changes, or overripeness ovopathy [8]. The 1.5e1.6 Mb 15q24 deletion in our patient lies within recurrent breakpoints recently described as “BP1” and “BP2” [9].
A. Brun et al. / European Journal of Medical Genetics 55 (2012) 135e139
137
Fig. 2. Array-CGH (comparative genomic hybridization) analysis. Genomic DNA of the patient was hybridized against a reference DNA. A) Chromosomal view. The grey line indicates the deleted region. B) Gene view. Each dot represents an oligonucleotide probe. Blue boxes represent genes. The results are expressed as the log2 of the ratio. A) 0.7 to 1.2 ratio indicates that the oligonucleotide is deleted.
These regions correspond to highly identical segmental duplications, thus suggesting that a classical non-allelic homologous recombination occurred in this patient. This 1.6 Mb deletion represents the minimal critical region described in the 15q24 syndrome. More recently, a finest breakpoint mapping led to identification of other LCR clusters inside the 15q24 region, that could lead to alternative sized aberrations [7]. The minimal deleted region in our patient contained 37 RefSeq genes (Fig. 3). Among these genes, 3 genes are already involved in autosomal recessive disorders: STRA6 in syndromic microphtalmia, CYP11A1 in congenital adrenal hyperplasia with sex reversal, and MPI in a congenital disorder of glycosylation type 1B. Proteins encoded by other genes in the region are involved in diverse functions [7], such as neural development and neurotransmitter release (SEMA7A and CPLX3, that could explain mental retardation), synthesis of steroid hormones, mRNA and tRNA maturation, biosynthesis of coenzyme A, base-excision repair of damaged DNA, transcription repression, participation in the formation of the histone deacetylase complex (SIN3A), antioncogene function (CSK).
Interestingly, the phenotype associated with the recurrent 15q24 deletion syndrome is quite heterogeneous and can occasionally include features of OAVS, such as facial asymmetry, ear dysplasia, and deafness [10]; however, grade IV microtia has never been observed in this new microdeletional syndrome. OAVS is an extremely complex and heterogeneous condition. Minimal diagnostic criteria are still a matter of discussion, and usually include unilateral microtia and hemifacial microsomia, even without ocular or vertebral anomalies [2,3]. Ear abnormalities are variable, and often under-evaluated in patients [11]. Indeed, such minimal and poorly characterized features could be present in other syndromes with multiple congenital anomalies. Complex aetiology in OAVS has been reinforced by a recent study with genome-wide scanning in one family with 5 affected probands [12]. We tend to believe that features of OAVS observed in our patient are part of the 15q24 microdeletion syndrome. This could mean that the deleted region include a gene involved in the embryonic development of the ears and face. Owing to the genetic
138
A. Brun et al. / European Journal of Medical Genetics 55 (2012) 135e139
Fig. 3. Chromosomal map (from UCSC genome browser) showing patient’s minimal deletion in 15q24.1q24.2 region including 37 genes. Two BAC probes used for FISH analyses are bordered in red.
heterogeneity and to the frequency of gene dosage anomalies associated with OAVS, array-CGH appears to be essential in the diagnosis screening of the patients presenting with features of OAVS. Other observations are needed in order to make more accurate genotype-phenotype correlations.
Acknowledgments
Table 1 Clinical features of OAVS, 15q24 deletion syndrome, and our patient.
References
Clinical features
OAVS
15q24 deletion syndrome
Present case
Intrauterine growth retardation Neonatal hypotonia Microtia Preauricular tag Facial asymmetry Hemifacial microsomia Mandibular/malar hypoplasia Ocular defects Vertebral anomalies Hearing loss Orofacial clefts Growth retardation Intellectual disability Facial dysmorphism: -Hypertelorism -Depressed nasal bridge -Macrostomia -Long narrow face -Broad medial eyebrows -High anterior hairline
þ þ þ þ þ þ þ þ þ rare mild þ þ þ
þ þ þ þ rare þ þ þ þ þ þ þ þ þ
þ þ þ þ þ þ þ þ þ þ þ þ þ þ
The authors thank the patient, the French Ministry of Research of France, the French Ministry of Health, the GIS Maladies Rares and the Association Française contre les Myopathies for their financial support.
[1] M. Goldenhar, Associations malformatives de l’oeil et de l’oreille, en particulier le syndrome dermoïde épibulbaire-appendices auriculaires-fistula auris congenita et ses relations avec la dysostose mandibulo-faciale, J. Genet. Hum. 1 (1952) 243e282. [2] C. Tasse, S. Bohringer, S. Fischer, H.J. Ludecke, B. Albrecht, D. Horn, A. Janecke, R. Kling, R. Konig, B. Lorenz, F. Majewski, E. Maeyens, P. Meinecke, B. Mitulla, C. Mohr, M. Preischl, H. Umstadt, J. Kohlhase, G. Gillessen-Kaesbach, D. Wieczorek, Oculo-auriculo-vertebral spectrum (OAVS): clinical evaluation and severity scoring of 53 patients and proposal for a new classification, Eur. J. Med. Genet. 48 (2005) 397e411. [3] R.C. Hennekam, I.D. Krantz, J.E. Allanson, Gorlin’s syndromes of the head and neck, Oxford, New York, 2010. [4] S. Vendramini-Pittoli, N.M. Kokitsu-Nakata, Oculoauriculovertebral spectrum: report of nine familial cases with evidence of autosomal dominant inheritance and review of the literature, Clin. Dysmorphol. 18 (2009) 67e77. [5] C. Rooryck, N. Souakri, D. Cailley, J. Bouron, C. Goizet, M.A. Delrue, S. Marlin, F.D. Lacombe, B. Arveiler, Array-CGH analysis of a cohort of 86 patients with oculoauriculovertebral spectrum, Am. J. Med. Genet. A 152A (2010) 1984e1989. [6] S. Fischer, H.J. Ludecke, D. Wieczorek, S. Bohringer, G. Gillessen-Kaesbach, B. Horsthemke, Histone acetylation dependent allelic expression imbalance of BAPX1 in patients with the oculo-auriculo-vertebral spectrum, Hum. Mol. Genet. 15 (2006) 581e587. [7] A.W. El-Hattab, T.A. Smolarek, M.E. Walker, E.K. Schorry, L.L. Immken, G. Patel, M.A. Abbott, B.C. Lanpher, Z. Ou, S.H. Kang, A. Patel, F. Scaglia, J.R. Lupski,
A. Brun et al. / European Journal of Medical Genetics 55 (2012) 135e139 S.W. Cheung, P. Stankiewicz, Redefined genomic architecture in 15q24 directed by patient deletion/duplication breakpoint mapping, Hum. Genet. 126 (2009) 589e602. [8] D. Wieczorek, M. Ludwig, S. Boehringer, P.H. Jongbloet, G. Gillessen-Kaesbach, B. Horsthemke, Reproduction abnormalities and twin pregnancies in parents of sporadic patients with oculo-auriculo-vertebral spectrum/Goldenhar syndrome, Hum. Genet. 121 (2007) 369e376. [9] A.J. Sharp, R.R. Selzer, J.A. Veltman, S. Gimelli, G. Gimelli, P. Striano, A. Coppola, R. Regan, S.M. Price, N.V. Knoers, P.S. Eis, H.G. Brunner, R.C. Hennekam, S.J. Knight, B.B. de Vries, O. Zuffardi, E.E. Eichler, Characterization of a recurrent 15q24 microdeletion syndrome, Hum. Mol. Genet. 16 (2007) 567e572.
139
[10] L.A. McInnes, A. Nakamine, M. Pilorge, T. Brandt, P. Jimenez Gonzalez, M. Fallas, E.R. Manghi, L. Edelmann, J. Glessner, H. Hakonarson, C. Betancur, J.D. Buxbaum, A large-scale survey of the novel 15q24 microdeletion syndrome in autism spectrum disorders identifies an atypical deletion that narrows the critical region, Mol. Autism. 1 (2010) 5. [11] R.F. Rosa, A.P. Silva, T.B. Goetze, A. Bier Bde, S.T. Almeida, G.A. Paskulin, P.R. Zen, Ear abnormalities in patients with oculo-auriculo-vertebral spectrum (Goldenhar syndrome), Braz. J. Otorhinolaryngol. 77 (2011) 455e460. [12] X.S. Huang, X. Li, C. Tan, L. Xiao, H.O. Jiang, S.F. Zhang, D.M. Wang, J.X. Zhang, Genome-wide scanning reveals complex etiology of oculo-auriculo-vertebral spectrum, Tohoku J. Exp. Med. 222 (2010) 311e318.
Contents lists available at SciVerse ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Chromosomal imbalance letter
1.5 Mb microdeletion in 15q24 in a patient with mild OAVS phenotype Aurore Brun a, Dorothée Cailley a, Jérôme Toutain a, Julie Bouron a, Benoit Arveiler a, b, Didier Lacombe a, b, Cyril Goizet a, b, Caroline Rooryck a, b, * a b
CHU Bordeaux, Department of Medical Genetics, Bordeaux, France Univ. Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM), EA 4576, F-33000 Bordeaux, France
a r t i c l e i n f o
a b s t r a c t
Article history: Received 8 September 2011 Accepted 20 November 2011 Available online 3 December 2011
We report on a boy presenting with features of OAVS (Oculoauriculovertebral spectrum) and carrying a 1.5 Mb microdeletion in 15q24.1q24.2. This recurrent deletion usually leads to a broad clinical spectrum but has never been found associated with features of OAVS such as ear agenesis. This observation is in accordance with OAVS being a genetically heterogeneous disorder, and points out the importance of array-CGH screening in this disorder. Ó 2011 Elsevier Masson SAS. All rights reserved.
Keywords: 15q24 microdeletion Goldenhar syndrome Oculoauriculovertebral spectrum Array-CGH Facial asymmetry Anotia Microtia
1. Introduction Oculoauriculovertebral spectrum (OAVS, OMIM 164210) is a developmental disorder involving the first and second branchial arches during embyogenesis. This spectrum includes conditions previously known as hemifacial microsomia and Goldenhar syndrome [1], and is clinically heterogeneous, ranging from isolated unilateral microtia to multiple visceral malformations. Main features are unilateral or bilateral ear anomalies (anotia, microtia, preauricular tags, and pits, ear dysplasia), hemifacial microsomia, ocular defects (coloboma of upper eyelid, epibulbar dermoids, microphthalmia), conductive and/or sensorineural hearing loss, orofacial clefts, vertebral malformations, and more rarely, cardiac, renal and cerebral malformations with possible mental retardation [2]. OAVS incidence has been estimated to 1/5,600 [3]. The majority of cases appear to be sporadic. Among the genetic forms of OAVS, familial cases are mostly in favor of a dominant autosomal transmission with incomplete penetrance and variable expressivity [4]. Chromosomal abnormalities associated with OAVS are numerous including trisomies, as well as intrachromosomal deletions and duplications, that are either inherited or de novo [5]. Epigenic pathogeny has also been suggested in the BAPX1 gene [6]. * Corresponding author. Laboratoire Maladies Rares: Génétique et Métabolisme, Université Bordeaux Segalen, Bordeaux, France. Tel.: þ33 557820357; fax: þ33 556795648. E-mail address: [email protected] (C. Rooryck). 1769-7212/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2011.11.006
However, to date, no specific gene has been involved in OAVS. Here, we describe one patient with features of OAVS, carrying a de novo deletion in 15q24.1q24.2. 2. Methods of detection 2.1. Cytogenetics Chromosome analysis was performed on peripheral blood lymphocyte cultures using conventional techniques. Chromosomes were then treated with 5-Bromodeoxyuridine, exposed to light and heat, and colored using Giemsa stains (RBG-bands). Karyotypes were established at a level of resolution of up to 550 bands per haploid set. The conventional cytogenetic analysis did not reveal any abnormality. 2.2. Array-CGH Was performed on DNA extracted from peripheral blood, using 8 60 K Oligonucleotide microarrays (Agilent Technologies Santa Clara, California). 2.3. Chromosomal anomaly Deletion occurred in chromosomal band 15q24.1q24.2 (Figs. 2 and 3), with deleted flanking probes: A_14_P131807 (centromeric)
136
A. Brun et al. / European Journal of Medical Genetics 55 (2012) 135e139
Fig. 1. Facial features of the patient at age of 24 years. A) Face view. Notice facial asymmetry and dysmorphic features typical of 15q24 deletion syndrome, including high anterior hairline, long narrow face, and broad medial eyebrows B. Profile view. Notice right ear agenesis.
and A_14_P109620 telomeric. Size of the deletion is between 1.51 and 1.62 Mb. The genomic coordinates of centromeric breakpoint are between 74,328,437 (not deleted) and 74,419,546 (deleted) and the telomeric breakpoint is between 75,931,476 (deleted) and 75,950,540 (not deleted) (Hg19).
bulbous nose, broad medial eyebrows, high anterior hairline, and long narrow face (Fig. 1). At last investigation, the patient was 24 years-old and his growth delay was persistent: weight was 40 kg (3 SD) and height was 162 cm (2.5 SD). He had myopia and strabismus. Mental retardation was mild (IQw74). He had neither vertebral nor cardiac anomalies.
2.4. Method of confirmation 4. Discussion The presence of the deletion was confirmed by FISH using probes BAC RP11-10O17 in 15q24.1 and BAC RP11-69H7 in 15q24.2 (Amplitech)(data available upon request). 2.5. Causative of the phenotype? 15q24 deletion occurred de novo, as both parents were investigated by FISH using the two same probes and no deletion was found. 3. Clinical description We describe a boy born from young and healthy non consanguineous parents (mother and father of 30 and 33 years-old respectively). He had a healthy twin sister. The pregnancy was uneventful, except for intrauterine growth retardation observed during the third trimester. In particular, there was no gestational diabetes, neither toxic exposure of the mother. He was born at 37 weeks of gestation after delivery by Caesarian section due to a transverse position. At birth, weight was 2.240 kg (2 SD), height was 48 cm (2 SD) and head circumference 33.5 cm (1.5 SD). He had hypotonia and presented two consecutive circulatory arrests, in the first weeks of life. He suffered from acute dyspnea, recurrent respiratory infections, and gastrointestinal reflux. He had moderate psychomotor delay and walked unaided at 18 months. He presented with cleft of the soft palate, right grade IV microtia and hemifacial microsomia due to malar and mandibular hypoplasia. He had bilateral conductive hearing loss (no audition on the right side due to agenesis of external auditory canal and a threshold of 50 db on the left ear) and had a hearing aid. Facial dysmorphism included
To our knowledge, our propositus is the first patient described with features of OAVS such as ear agenesis (grade IV microtia), hearing loss, hemifacial microsomia, and cleft palate, associated with a de novo deletion in 15q24.1q24.2. A recent publication describing a cohort of 86 OAVS analyzed by oligonucleotide arrayCGH, identified 12 rearrangements in different chromosomal regions, but no 15q24 deletion [5]. Our patient also presented with features usually associated with 15q24 deletion such as neonatal hypotonia, growth retardation, mental retardation, and typical facial dysmorphism (including long narrow face, broad medial eyebrows, and high anterior hairline). Table 1 summarizes clinical features of our patient compared to features of OAVS and of 15q24 deletion syndrome. Interestingly, some ear abnormalities are described in the 15q24 clinical spectrum such as ear lobe pit, cupshaped protruding ears, large or small everted ears; however unilateral grade IV microtia has never been described [7]. One additional patient has been described in the Decipher database with “low-set ears” and “external ears abnormalities”. Interestingly, our patient had a dizygotic twin. Twinning is frequently associated with OAVS condition. Several hypothesis have been enounced: the embryologic defect in OAVS could cause twinning for example via an imprinting defect causing asymmetry, or twinning could increase the risk for OAVS through abnormal vascular supply of the head (vascular disruption theory), or finally OAVS and monozygotic twinning could have a common basis due to an early malformation complex, early epigenetic changes, or overripeness ovopathy [8]. The 1.5e1.6 Mb 15q24 deletion in our patient lies within recurrent breakpoints recently described as “BP1” and “BP2” [9].
A. Brun et al. / European Journal of Medical Genetics 55 (2012) 135e139
137
Fig. 2. Array-CGH (comparative genomic hybridization) analysis. Genomic DNA of the patient was hybridized against a reference DNA. A) Chromosomal view. The grey line indicates the deleted region. B) Gene view. Each dot represents an oligonucleotide probe. Blue boxes represent genes. The results are expressed as the log2 of the ratio. A) 0.7 to 1.2 ratio indicates that the oligonucleotide is deleted.
These regions correspond to highly identical segmental duplications, thus suggesting that a classical non-allelic homologous recombination occurred in this patient. This 1.6 Mb deletion represents the minimal critical region described in the 15q24 syndrome. More recently, a finest breakpoint mapping led to identification of other LCR clusters inside the 15q24 region, that could lead to alternative sized aberrations [7]. The minimal deleted region in our patient contained 37 RefSeq genes (Fig. 3). Among these genes, 3 genes are already involved in autosomal recessive disorders: STRA6 in syndromic microphtalmia, CYP11A1 in congenital adrenal hyperplasia with sex reversal, and MPI in a congenital disorder of glycosylation type 1B. Proteins encoded by other genes in the region are involved in diverse functions [7], such as neural development and neurotransmitter release (SEMA7A and CPLX3, that could explain mental retardation), synthesis of steroid hormones, mRNA and tRNA maturation, biosynthesis of coenzyme A, base-excision repair of damaged DNA, transcription repression, participation in the formation of the histone deacetylase complex (SIN3A), antioncogene function (CSK).
Interestingly, the phenotype associated with the recurrent 15q24 deletion syndrome is quite heterogeneous and can occasionally include features of OAVS, such as facial asymmetry, ear dysplasia, and deafness [10]; however, grade IV microtia has never been observed in this new microdeletional syndrome. OAVS is an extremely complex and heterogeneous condition. Minimal diagnostic criteria are still a matter of discussion, and usually include unilateral microtia and hemifacial microsomia, even without ocular or vertebral anomalies [2,3]. Ear abnormalities are variable, and often under-evaluated in patients [11]. Indeed, such minimal and poorly characterized features could be present in other syndromes with multiple congenital anomalies. Complex aetiology in OAVS has been reinforced by a recent study with genome-wide scanning in one family with 5 affected probands [12]. We tend to believe that features of OAVS observed in our patient are part of the 15q24 microdeletion syndrome. This could mean that the deleted region include a gene involved in the embryonic development of the ears and face. Owing to the genetic
138
A. Brun et al. / European Journal of Medical Genetics 55 (2012) 135e139
Fig. 3. Chromosomal map (from UCSC genome browser) showing patient’s minimal deletion in 15q24.1q24.2 region including 37 genes. Two BAC probes used for FISH analyses are bordered in red.
heterogeneity and to the frequency of gene dosage anomalies associated with OAVS, array-CGH appears to be essential in the diagnosis screening of the patients presenting with features of OAVS. Other observations are needed in order to make more accurate genotype-phenotype correlations.
Acknowledgments
Table 1 Clinical features of OAVS, 15q24 deletion syndrome, and our patient.
References
Clinical features
OAVS
15q24 deletion syndrome
Present case
Intrauterine growth retardation Neonatal hypotonia Microtia Preauricular tag Facial asymmetry Hemifacial microsomia Mandibular/malar hypoplasia Ocular defects Vertebral anomalies Hearing loss Orofacial clefts Growth retardation Intellectual disability Facial dysmorphism: -Hypertelorism -Depressed nasal bridge -Macrostomia -Long narrow face -Broad medial eyebrows -High anterior hairline
þ þ þ þ þ þ þ þ þ rare mild þ þ þ
þ þ þ þ rare þ þ þ þ þ þ þ þ þ
þ þ þ þ þ þ þ þ þ þ þ þ þ þ
The authors thank the patient, the French Ministry of Research of France, the French Ministry of Health, the GIS Maladies Rares and the Association Française contre les Myopathies for their financial support.
[1] M. Goldenhar, Associations malformatives de l’oeil et de l’oreille, en particulier le syndrome dermoïde épibulbaire-appendices auriculaires-fistula auris congenita et ses relations avec la dysostose mandibulo-faciale, J. Genet. Hum. 1 (1952) 243e282. [2] C. Tasse, S. Bohringer, S. Fischer, H.J. Ludecke, B. Albrecht, D. Horn, A. Janecke, R. Kling, R. Konig, B. Lorenz, F. Majewski, E. Maeyens, P. Meinecke, B. Mitulla, C. Mohr, M. Preischl, H. Umstadt, J. Kohlhase, G. Gillessen-Kaesbach, D. Wieczorek, Oculo-auriculo-vertebral spectrum (OAVS): clinical evaluation and severity scoring of 53 patients and proposal for a new classification, Eur. J. Med. Genet. 48 (2005) 397e411. [3] R.C. Hennekam, I.D. Krantz, J.E. Allanson, Gorlin’s syndromes of the head and neck, Oxford, New York, 2010. [4] S. Vendramini-Pittoli, N.M. Kokitsu-Nakata, Oculoauriculovertebral spectrum: report of nine familial cases with evidence of autosomal dominant inheritance and review of the literature, Clin. Dysmorphol. 18 (2009) 67e77. [5] C. Rooryck, N. Souakri, D. Cailley, J. Bouron, C. Goizet, M.A. Delrue, S. Marlin, F.D. Lacombe, B. Arveiler, Array-CGH analysis of a cohort of 86 patients with oculoauriculovertebral spectrum, Am. J. Med. Genet. A 152A (2010) 1984e1989. [6] S. Fischer, H.J. Ludecke, D. Wieczorek, S. Bohringer, G. Gillessen-Kaesbach, B. Horsthemke, Histone acetylation dependent allelic expression imbalance of BAPX1 in patients with the oculo-auriculo-vertebral spectrum, Hum. Mol. Genet. 15 (2006) 581e587. [7] A.W. El-Hattab, T.A. Smolarek, M.E. Walker, E.K. Schorry, L.L. Immken, G. Patel, M.A. Abbott, B.C. Lanpher, Z. Ou, S.H. Kang, A. Patel, F. Scaglia, J.R. Lupski,
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