RESEARCH ARTICLE
Inversion Duplication Deletions Involving the Long Arm of Chromosome 13: Phenotypic Description of Additional Three Fetuses and Genotype– Phenotype Correlation Chloe Quelin,1,2 Emmanuel Spaggiari,1 Suonavy Khung-Savatovsky,1 Celine Dupont,3 Laurent Pasquier,2 Laurence Loeuillet,4 Sylvie Jaillard,5 Josette Lucas,5 Pascale Marcorelles,6 Hubert Journel,7 Khantaby Pluquailec-Bilavarn,8 Anne Bazin,9 Alain Verloes,10 Anne-Lise Delezoide,1 Azzedine Aboura,3 and Fabien Guimiot1* 1
Department of Developmental Biology, AP-HP, Robert Debre´ University Hospital, Paris and Diderot University, Paris, France Clinical Genetics Unit, Rennes Sud University Hospital, Rennes, France 3 Cytogenetics Unit, AP-HP, Robert Debre´ University Hospital, Paris Diderot University, Paris, France 2
4
Pathology Laboratory, Poissy Hospital, Saint Germain en Laye, France Cytogenetics Unit, Rennes Pontchaillou University Hospital, Rennes, France
5 6
Pathology Laboratory, Pole Pathologie-Biologie, Brest University Hospital, Brest, France
7
Clinical Genetics Unit, CHBA, Chubert Hospital, Vannes, France Cytogenetics Laboratory, Cesson-Se´vigne´, France
8 9
Cerba Laboratory, Cergy-Pontoise, France
10
Department of Genetic, AP-HP, Robert Debre´ University Hospital, Paris and Diderot University, Paris, France
Manuscript Received: 10 June 2013; Manuscript Accepted: 28 May 2014
Inversion duplication and terminal deletion of the long arm of chromosome 13 (inv dup del 13q) is a rare chromosomal rearrangement: only five patients have been reported, mostly involving a ring chromosome 13. We report on additional three fetuses with pure inv dup del 13q: Patient 1 had macrosomia, enlarged kidneys, hypersegmented lungs, unilateral moderate ventriculomegaly, and a mild form of hand and feet preaxial polydactyly; Patient 2 had intrauterine growth retardation, widely spaced eyes, left microphthalmia, right anophthalmia, short nose, bilateral absent thumbs, cutaneous syndactyly of toes 4 and 5, bifid third metacarpal, a small left kidney, hyposegmented lungs, and partial agenesis of the corpus callosum; Patient 3 had widely spaced eyes, long and smooth philtrum, low-set ears, median notch in the upper alveolar ridge, bifid tongue, cutaneous syndactyly of toes 2 and 3, enlarged kidneys and pancreas, arhinencephaly, and partial agenesis of the corpus callosum. We compared the phenotypes of these patients to those previously reported for ring chromosome 13, pure 13q deletions and duplications. We narrowed some critical regions previously reported for lung, kidney and fetal growth, and for thumb, cerebral, and eye anomalies. Ó 2014 Wiley Periodicals, Inc.
Key words: prenatal; inv dup del 13q; phenotype Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Quelin C, Spaggiari E, Khung-Savatovsky S, Dupont C, Pasquier L, Loeuillet L, Jaillard S, Lucas J, Marcorelles P, Journel H, Pluquailec-Bilavarn K, Bazin A, Verloes A, Delezoide A-L, Aboura A, Guimiot F. 2014. Inversion duplication deletions involving the long arm of chromosome 13: phenotypic description of additional three fetuses and genotype–phenotype correlation. Am J Med Genet Part A 164A:2504–2509.
Conflict of interest: none. Correspondence to: Dr. Fabien Guimiot, Ph.D., Department of Developmental Biology, APHP, Robert Debre´ Hospital, 48 Boulevard Se´rurier, 75019 Paris, France. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 26 June 2014 DOI 10.1002/ajmg.a.36658
2504
QUELIN ET AL.
INTRODUCTION The 13q deletion syndrome is characterized by moderate to severe intellectual disability, growth delay, dysmorphic facial features, limb anomalies and malformations of brain, eye, kidney, or heart, according to the size of the deleted region [Lyons Jones, 1997]. Several genes such as ZIC2 and RB1 are well-established genes for holoprosencephaly (HPE) [Brown et al., 1998] and retinoblastoma [Lohmann and Gallie, 2004], respectively. Other genes have been suggested as candidates for the other malformations. For example, EFNB2 is a candidate for genital malformations in males and ARHGEF7 for intellectual disability and microcephaly [WalczakSztulpa et al., 2008]. However, the information that can be obtained from genotype to phenotype correlations remains limited because the syndrome is rare, and there have been few reported patients. Inverted duplications contiguous to distal deletions (inv dup del) are complex rearrangements, and can now be detected and described with greater accuracy by molecular karyotyping. Microarray analysis allows precise quantitation of the boundaries of deleted and duplicated segments. These abnormalities have been identified and characterized in many chromosomes and seem to be more frequent than was suggested by conventional cytogenetics [Rowe et al., 2009; Zuffardi et al., 2009]. To date, four diagnosed patients with Inv dup del 13q have been reported with ring chromosomes [Shimokawa et al., 2004; Rowe et al., 2009], one in association with a duplication of the terminal region of the short arm of chromosome 4 [Rossi et al., 2008; Rowe et al., 2009; Yu and Graf, 2010] and one pure prenatal case [Jonch et al., 2012]. We report an additional three fetuses with pure inv dup del 13q and their characterization by microarray. We attempted to associate phenotypic features to haploinsufficiency or overexpression of critical regions or genes in chromosome 13 by comparing these patients to those reported in the literature, with pure inv up del 13q, inv dup del 13q with ring chromosome 13, pure 13q deletions and duplications.
CLINICAL REPORTS Patient 1 The patient was delivered by medical termination of pregnancy (TOP) at 32 weeks of gestation (WG) from a gravida 2 para 1 mother. Ultrasound scanning at 22 WG showed right cerebral ventriculomegaly (10 mm: >90th centile). Karyotyping of amniotic fluid cells was abnormal with additional material on the long arm of chromosome 13. The fetus was female, weighed 2,210 g (>90th centile, mean weight for 35 WG) with a crown-heel length of 33 cm (75th–95th centiles). She was not dysmorphic. The thumbs and halluces appeared broad. At autopsy, the kidneys were enlarged (18.6 g for the left and 19 g for the right, corresponding to the 95th centiles for 40 and 41 WG) and the lungs had one supernumerary lobar fissure (Supplemental Online Fig. S1A). Neuropathological examination confirmed right ventriculomegaly (Supplemental Online Fig. S1B) and the anterior part of the falx cerebri was abnormally short. Histological examination showed heterotopic neuroglial tissue in front of the optic tracts, and one nodule of heterotopia in the vermis. X-rays showed long bone length and maturation consistent with the gestational age. The distal
2505 phalanges of the thumbs and halluces were bifid (Supplemental Online Fig. S1C and D) causing a mild form of hand and feet preaxial polydactyly. The placenta was mildly enlarged (438 g, mean weight for 35–36 WG) with velamentous insertion of the umbilical cord.
Patient 2 The patient was delivered by medical TOP at 23 WG from a gravida 1 para 1 mother. Ultrasound scanning at 22 WG showed complete agenesis of the corpus callosum and oligodactyly. Karyotyping with amniotic fluid cells found partial 13q monosomy. The fetus was female, weighed 425 g (10th centile) and had a crown-heel length of 28 cm (10th centile). She had widely spaced eyes, left microphthalmia, right anophthalmia, a short nose, bilateral absent thumbs (Supplemental Online Fig. S1E), bilateral single transverse palmar creases and cutaneous syndactyly of toes 4 and 5 (Supplemental Online Fig. S1F). She had anteposed and atretic anus, vaginal prolapse (Supplemental Online Fig. S1G) and bicornuate uterus unicollis. The left kidney was small (1.25 g,
Inversion Duplication Deletions Involving the Long Arm of Chromosome 13: Phenotypic Description of Additional Three Fetuses and Genotype– Phenotype Correlation Chloe Quelin,1,2 Emmanuel Spaggiari,1 Suonavy Khung-Savatovsky,1 Celine Dupont,3 Laurent Pasquier,2 Laurence Loeuillet,4 Sylvie Jaillard,5 Josette Lucas,5 Pascale Marcorelles,6 Hubert Journel,7 Khantaby Pluquailec-Bilavarn,8 Anne Bazin,9 Alain Verloes,10 Anne-Lise Delezoide,1 Azzedine Aboura,3 and Fabien Guimiot1* 1
Department of Developmental Biology, AP-HP, Robert Debre´ University Hospital, Paris and Diderot University, Paris, France Clinical Genetics Unit, Rennes Sud University Hospital, Rennes, France 3 Cytogenetics Unit, AP-HP, Robert Debre´ University Hospital, Paris Diderot University, Paris, France 2
4
Pathology Laboratory, Poissy Hospital, Saint Germain en Laye, France Cytogenetics Unit, Rennes Pontchaillou University Hospital, Rennes, France
5 6
Pathology Laboratory, Pole Pathologie-Biologie, Brest University Hospital, Brest, France
7
Clinical Genetics Unit, CHBA, Chubert Hospital, Vannes, France Cytogenetics Laboratory, Cesson-Se´vigne´, France
8 9
Cerba Laboratory, Cergy-Pontoise, France
10
Department of Genetic, AP-HP, Robert Debre´ University Hospital, Paris and Diderot University, Paris, France
Manuscript Received: 10 June 2013; Manuscript Accepted: 28 May 2014
Inversion duplication and terminal deletion of the long arm of chromosome 13 (inv dup del 13q) is a rare chromosomal rearrangement: only five patients have been reported, mostly involving a ring chromosome 13. We report on additional three fetuses with pure inv dup del 13q: Patient 1 had macrosomia, enlarged kidneys, hypersegmented lungs, unilateral moderate ventriculomegaly, and a mild form of hand and feet preaxial polydactyly; Patient 2 had intrauterine growth retardation, widely spaced eyes, left microphthalmia, right anophthalmia, short nose, bilateral absent thumbs, cutaneous syndactyly of toes 4 and 5, bifid third metacarpal, a small left kidney, hyposegmented lungs, and partial agenesis of the corpus callosum; Patient 3 had widely spaced eyes, long and smooth philtrum, low-set ears, median notch in the upper alveolar ridge, bifid tongue, cutaneous syndactyly of toes 2 and 3, enlarged kidneys and pancreas, arhinencephaly, and partial agenesis of the corpus callosum. We compared the phenotypes of these patients to those previously reported for ring chromosome 13, pure 13q deletions and duplications. We narrowed some critical regions previously reported for lung, kidney and fetal growth, and for thumb, cerebral, and eye anomalies. Ó 2014 Wiley Periodicals, Inc.
Key words: prenatal; inv dup del 13q; phenotype Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Quelin C, Spaggiari E, Khung-Savatovsky S, Dupont C, Pasquier L, Loeuillet L, Jaillard S, Lucas J, Marcorelles P, Journel H, Pluquailec-Bilavarn K, Bazin A, Verloes A, Delezoide A-L, Aboura A, Guimiot F. 2014. Inversion duplication deletions involving the long arm of chromosome 13: phenotypic description of additional three fetuses and genotype–phenotype correlation. Am J Med Genet Part A 164A:2504–2509.
Conflict of interest: none. Correspondence to: Dr. Fabien Guimiot, Ph.D., Department of Developmental Biology, APHP, Robert Debre´ Hospital, 48 Boulevard Se´rurier, 75019 Paris, France. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 26 June 2014 DOI 10.1002/ajmg.a.36658
2504
QUELIN ET AL.
INTRODUCTION The 13q deletion syndrome is characterized by moderate to severe intellectual disability, growth delay, dysmorphic facial features, limb anomalies and malformations of brain, eye, kidney, or heart, according to the size of the deleted region [Lyons Jones, 1997]. Several genes such as ZIC2 and RB1 are well-established genes for holoprosencephaly (HPE) [Brown et al., 1998] and retinoblastoma [Lohmann and Gallie, 2004], respectively. Other genes have been suggested as candidates for the other malformations. For example, EFNB2 is a candidate for genital malformations in males and ARHGEF7 for intellectual disability and microcephaly [WalczakSztulpa et al., 2008]. However, the information that can be obtained from genotype to phenotype correlations remains limited because the syndrome is rare, and there have been few reported patients. Inverted duplications contiguous to distal deletions (inv dup del) are complex rearrangements, and can now be detected and described with greater accuracy by molecular karyotyping. Microarray analysis allows precise quantitation of the boundaries of deleted and duplicated segments. These abnormalities have been identified and characterized in many chromosomes and seem to be more frequent than was suggested by conventional cytogenetics [Rowe et al., 2009; Zuffardi et al., 2009]. To date, four diagnosed patients with Inv dup del 13q have been reported with ring chromosomes [Shimokawa et al., 2004; Rowe et al., 2009], one in association with a duplication of the terminal region of the short arm of chromosome 4 [Rossi et al., 2008; Rowe et al., 2009; Yu and Graf, 2010] and one pure prenatal case [Jonch et al., 2012]. We report an additional three fetuses with pure inv dup del 13q and their characterization by microarray. We attempted to associate phenotypic features to haploinsufficiency or overexpression of critical regions or genes in chromosome 13 by comparing these patients to those reported in the literature, with pure inv up del 13q, inv dup del 13q with ring chromosome 13, pure 13q deletions and duplications.
CLINICAL REPORTS Patient 1 The patient was delivered by medical termination of pregnancy (TOP) at 32 weeks of gestation (WG) from a gravida 2 para 1 mother. Ultrasound scanning at 22 WG showed right cerebral ventriculomegaly (10 mm: >90th centile). Karyotyping of amniotic fluid cells was abnormal with additional material on the long arm of chromosome 13. The fetus was female, weighed 2,210 g (>90th centile, mean weight for 35 WG) with a crown-heel length of 33 cm (75th–95th centiles). She was not dysmorphic. The thumbs and halluces appeared broad. At autopsy, the kidneys were enlarged (18.6 g for the left and 19 g for the right, corresponding to the 95th centiles for 40 and 41 WG) and the lungs had one supernumerary lobar fissure (Supplemental Online Fig. S1A). Neuropathological examination confirmed right ventriculomegaly (Supplemental Online Fig. S1B) and the anterior part of the falx cerebri was abnormally short. Histological examination showed heterotopic neuroglial tissue in front of the optic tracts, and one nodule of heterotopia in the vermis. X-rays showed long bone length and maturation consistent with the gestational age. The distal
2505 phalanges of the thumbs and halluces were bifid (Supplemental Online Fig. S1C and D) causing a mild form of hand and feet preaxial polydactyly. The placenta was mildly enlarged (438 g, mean weight for 35–36 WG) with velamentous insertion of the umbilical cord.
Patient 2 The patient was delivered by medical TOP at 23 WG from a gravida 1 para 1 mother. Ultrasound scanning at 22 WG showed complete agenesis of the corpus callosum and oligodactyly. Karyotyping with amniotic fluid cells found partial 13q monosomy. The fetus was female, weighed 425 g (10th centile) and had a crown-heel length of 28 cm (10th centile). She had widely spaced eyes, left microphthalmia, right anophthalmia, a short nose, bilateral absent thumbs (Supplemental Online Fig. S1E), bilateral single transverse palmar creases and cutaneous syndactyly of toes 4 and 5 (Supplemental Online Fig. S1F). She had anteposed and atretic anus, vaginal prolapse (Supplemental Online Fig. S1G) and bicornuate uterus unicollis. The left kidney was small (1.25 g,
