Mb Interstitial Deletion at 10P11.22-P12.31

ORIGINAL ARTICLE

Prenatal and postnatal ﬁndings in a 10.6 Mb interstitial deletion at 10p11.22-p12.31

Simona Sosoi1,4, Ioana Streata1,4, Stefania Tudorache2, Florin Burada1, Mirela Siminel3, Nicolae Cernea2, Mihai Ioana1,5, Dominic Gabriel Iliescu2,5 and Francisc Mixich1,5

Interstitial deletion of the proximal short arm of chromosome 10 represents a rare genetic alteration. Literature review revealed that only 10 postnatal diagnosed clinical cases with deletions overlapping 10p12p11 were published until present. We report the ﬁrst prenatal diagnosis and postnatal ﬁndings in a male fetus with a 10.6 Mb interstitial deletion of the short arm of chromosome 10 (10p11.22-p12.31). Journal of Human Genetics (2015) 60, 183–185; doi:10.1038/jhg.2015.4; published online 5 February 2015

INTRODUCTION abnormalities were present (Figure 1): agenesis of ductus venosus, echogenic Although array comparative genomic hybridization (CGH) is nowa- intracardiac focus, clinodactily and micrognathia. days an important diagnostic tool in postnatal genetic pathologies that The 16 GW cytogenetic analyses suggested a deletion on the short arm of associate congenital malformations and mental retardation, it has not chromosome 10 (46, XY, 10p). At 22 GW, the morphological ultrasound evaluation revealed no major malformations but abnormal ultrasound genetic been widely used in the field of prenatal genetic diagnostics.1 Here we markers were again present (Figure 2): nuchal and prefrontal edema, ‘flat face’, report the prenatal diagnosis of an interstitial deletion located on the short femur and humerus and fetal growth restriction. Also, relative hyperte- short arm of chromosome 10 in a male fetus with sonographic lorism, persistent small stomach, persistent flexion of fingers and short feet abnormal genetic features and abnormal maternal serum biochem- were detected. istry. To our knowledge this is the first 10p interstitial deletion case Another amniocentesis was performed at 22 GW. The routine G-band identified prenatally, with amniotic fluid as the analyzed biologic analysis of cultured amniocytes depicted a 10p deletion. The result was further specimen. All previously reported cases were diagnosed and char- validated through array CGH (Figure 3), which accurately detected the genomic acterized after birth. Prenatal diagnosis is important, as the develop- size and gene content of the deleted region. After genetic counseling, the parents elected to continue the pregnancy. A mental delay, craniofacial abnormalities, cardiac malformation, fi late premature boy, with intrauterine growth restriction, was delivered by immune de ciencies and cryptorchidism are the main phenotypic cesarean section at 36 GW. Apgar scores were 6 and 7 at 1 and 5 min, features described in patients with deletions overlapping the proximal respectively. The neonatal evaluation revealed dysmorphic features including – 10p11–p12 region on the short arm of chromosome 10.2 4 frontal and parietal bossing with hypoplastic facial bones leading to a triangular face, aged face, low and flat nasal bridge, short nose with a bulbous nasal tip, MATERIALS AND METHODS hypertelorism, deeply set eyes, low-set ears with dysplastic helices, thin upper Amniocentesis was performed on a 31-year-old woman, at 16 weeks of lip, trismus, short trunk with a grade of contractures of thoracic cage, reflected gestation, after second trimester genetic risk calculation revealed low MOMs in reduced amplitude of breathing movements, short broad neck, hands in (multiple of median) of alpha fetoprotein (AFP) (0.43) and human chorionic ulnar deviation, camptodactyly and cryptorchidism (Figure 2). The newborn gonadotropin beta (hCGb) (0.57), 1.26 MOMs for unconjugated Estriol 3 presented fever syndrome of unknown etiology, intermittent hypoglycemic, (uE3) and increased risk for trisomy 21 (1/220). A previous scan at 12 feeding difficulties and respiratory problems related to superior airways gestational weeks (GW) had revealed increased fetal nuchal translucency hypoplasia. The growth curve was slow ascendant, 380 g gain in 8 weeks. (4.92 mm) and agenesis of ductus venosus (Figure 1). Invasive studies through The neonatal death occurred at the age of 8 weeks, due to an acute respiratory chorionic villus sampling showed no numerical abnormalities of 13, 18, 21, X failure exacerbated by a respiratory tract infection. The autopsy ascertained and Y chromosomes by quantitative fluorescence - polymerase chain reaction growth restriction and did not reveal other congenital malformations. (QF-PCR). Both parents were healthy, with no family history of genetic diseases or congenital malformations. RESULTS A detailed morphological evaluation was achieved during an early second The array CGH analysis, using a whole-genome 135 K oligonucleotide trimester ultrasound scan at 15 GW. Sonographic soft markers for genetic microarray platform (Roche NimbleGen, Madison, WI, USA),

1Human Genomics Laboratory, University of Medicine and Pharmacy Craiova, Craiova, Romania; 2Department of Obstetrics and Gynecology, Prenatal Diagnostic Unit, University of Medicine and Pharmacy Craiova, Craiova, Romania and 3Department of Neonatology, University of Medicine and Pharmacy Craiova, Craiova, Romania 4These authors contributed equally to this work. 5These authors contributed equally to this work. Correspondence: Dr M Ioana, Human Genomics Laboratory, University of Medicine and Pharmacy Craiova, 1 Mai Avenue, No 66, Craiova 200638, Romania. E-mail: [email protected] Received 2 September 2014; revised 22 December 2014; accepted 24 December 2014; published online 5 February 2015 Prenatal and postnatal ﬁndings in 10p11.22—p12.31 SSosoiet al 184

Figure 1 First (a–d) and second trimester (e–i) ultrasound genetic markers are 12 and 15 gestational weeks scan, respectively. (a) Increased nuchal translucency; (b) present nasal bone; (c) normal tricuspid ﬂow; (d) agenesis of ductus venosus in four-dimensional STIC power Doppler reconstruction; (e, f) abnormal facial sagittal plane, with micrognathiain two- and three-dimensional reconstruction of the fetal face; (g) echogenic intracardiac focus; (h) absence of the ductus venosus; and (i) clinodactily. H, heart; HV, hepatic veins; IVC, inferior vena cava; UA, umbilical arteries; UC, umbilical cord; UV, umbilical vein. A full color version of this ﬁgure is available at the Journal of Human Genetics journal online.

Figure 2 Supplementary ultrasound findings at the 22 GW scan (a–e) and postnatal features. (a) prefrontal edema; (b) hypertelorism; (c) increased nuchal fold; (d) persistent small stomach (arrow); (e) small and wide feet and abnormal persistent flexion of the hand fingers; (f, g) anterior and lateral aspect of the newborn. A full color version of this figure is available at the Journal of Human Genetics journal online.

detected a loss in 10p11.22—p12.31, encompassing a 10.6 Mb region of interstitial deletion of chromosome 10, but further cases with (chr10:21,461,075–32,075,988, hg19) within the proximal short arm of similar prenatal ﬁndings are expected to sustain our hypothesis. chromosome 10. Craniofacial dysmorphic features like deep-set eyes or bulbous nose were shared by our patient and seven of the previously diagnosed DISCUSSION cases.3–5 Comparative analysis of the array CGH results in these eight The above mentioned panel of dysmorphic features detected by patients revealed that the overlapping region has a length of 401 kb ultrasound might be considered as a pattern for the prenatal diagnosis and among the contained genes are BAMBI or WAC, suggested to be

Journal of Human Genetics Prenatal and postnatal ﬁndings in 10p11.22—p12.31 SSosoiet al 185

Figure 3 Array CGH result on chromosome 10. Image generated with Nexus 6.1 software (Nexus BioDiscovery, El Segundo, CA, USA). Data extraction (signal intensities) was performed with DEVA software (Roche Nimblegen). A full color version of this figure is available at the Journal of Human Genetics journal online. involved in the genetic etiology of developmental delay and cranio- the statement that proximal 10p deletion is a contiguous gene facial dysmorphic features like deeply set eyes, synophrys or bulbous syndrome. nasal tip.2,4 Cardiac abnormalities like conotruncal heart defects described in 7 out of 10 published cases with 10p interstitial deletion CONFLICT OF INTEREST have not been found in our patient despite the fact that he shared the The authors declare no conflict of interest. deletion of LYZL1 and SVIL genes. Cryptorchidism reported in three out of five reported males ACKNOWLEDGEMENTS with interstitial 10p deletion was also detected in our patient that For this paper IS was supported within the frame of European Social Found, shared the deletion of MKX gene found in the previous three Human Resources Development Operational Program 2007–2013, project no. cases, too.2,4 These findings suggest that MKX gene haploinsufficiency POSDRU/159/1.5/S/136893. could be involved in genetic susceptibility to cryptorchidism development. Comparative analyses of array CGH coupled with fine mapping of deleted regions, showed that our case and other 9 patients share an 1 Kleeman L., Bianchi D. W., Shaffer L. G., Rorem E., Cowan J., Craigo S. D. et al. Use of overlapping 711 kb deletion (chr10: 28802788-28091602—hg18). The array comparative genomic hybridization for prenatal diagnosis of fetuses with deleted region contains two protein-encoding genes: ARMC4 (arma- sonographic anomalies and normal metaphase karyotype. Prenat. Diagn. 29, 1213–1217 (2009). dillo repeat containing 4)andMPP7 (membrane protein, palmitoylated 2 Mroczkowski H. J., Arnold G., Schneck F. X., Rajkovic A. & Yatsenko S. A. Interstitial 7). It is therefore possible that defects of these genes be responsible for 10p11.23-p12.1 microdeletions associated with developmental delay, craniofacial craniofacial dysmorphism associated or not with developmental abnormalities, and cryptorchidism. Am. J. Med. Genet. A 164A, 2623–2626 (2014) 3 Okamoto, N., Hayashi, S., Masui, A., Kosaki, R., Oguri, I., Hasegawa, T. et al. Deletion disorders and mental impairment. at chromosome 10p11.23-p12.1 defines characteristic phenotypes with marked mid- We report, to our knowledge, the first prenatal case with a face retrusion. J. Hum. Genet. 57,191–196 (2012). 4 Wentzel C., Rajcan-Separovic E., Ruivenkamp C. A., Chantot-Bastaraud S., Metay C., deletion at 10p12p11 diagnosed through integrated cytogenetic Andrieux J. et al. Genomic and clinical characteristics of six patients with partially and genomic analyses. Our case together with the 10 previously overlapping interstitial deletions at 10p12p11. Eur. J. Hum. Genet. 19, published cases shared a similar clinical appearance characterized 959–964 (2011) 5 Shahdadpuri, R., de Vries, B., Pfundt, R., de Leeuw, N. & Reardon, W. Pseudoarthrosis by developmental delay and craniofacial dysmorphic features, prompt- of the clavicle and copper beaten skull associated with chromosome 10p11.21p12.1 ing us to define a genotype–phenotype correlation in order to sustain microdeletion. Am. J. Med. Genet. A 146A,233–237 (2008).

Journal of Human Genetics