Prenatal diagnosis and array comparative genomic hybridization characterization of a de novo X;Y translocation

RESEARCH LETTER

Prenatal diagnosis and array comparative genomic hybridization

characterization of a de novo X;Y translocation

Chih-Ping Chen

_{, Yi-Ning Su}

_{, Schu-Rern Chern}

_{, Jun-Wei Su}

_{, Yu-Ting Chen}

_,

Chen-Chi Lee

_{and Wayseen Wang}

a _{Department of Medicine, Mackay Medical College, New Taipei City, Taiwan}

b _{Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan} c _{Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan}

d _{Department of Biotechnology, Asia University, Taichung, Taiwan}

e _{School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan} f _{Institute of Clinical and Community Health Nursing, National Yang-Ming University, Taipei, Taiwan} g _{Department of Obstetrics and Gynecology, School of Medicine, National Yang-Ming University, Taipei,} Taiwan

h _{Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan}

i _{Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan} j _{Department of Bioengineering, Tatung University, Taipei, Taiwan}

* Correspondence to: Chih-Ping Chen, MD

Department of Obstetrics and Gynecology, Mackay Memorial Hospital 92, Section 2, Chung-Shan North Road, Taipei, Taiwan

Tel: +886-2-25433535; Fax: +886-2-25433642, +886-2-25232448 E-mail: [email protected]

Several types of X;Y translocations have been observed in humans. The first type is an Xp;Yq

translocation that produces a derivative X chromosome with a partial deletion of Xp and a partial

duplication of Yq such as 46,X,der(X)t(X;Y)(p22.3;q11) [1] and 46,X,der(Y)t(X;Y)(p22.3;q11)

[2]. The second type is a dicentric Xp;Yp translocation or a dicentric Xq;Yp translocation that

produces a dicentric X;Y chromosome with a Y chromosome attaching to the Xp or Xq breakpoint

at a Yp distal breakpoint such as 46,X,dic(X;Y)(p22.3;p11.2) [3] with a partial deletion of Xp and

a partial deletion of Yp on the dicentric X;Y chromosome, and 46,X,dic(X;Y)(q22;p11) [4] with a

partial deletion of Xq and a partial deletion of Yp on the dicentric X;Y chromosome. The third

type is an Xp;Yp translocation that produces a derivative X chromosome with a partial deletion of

Xp and a partial duplication of Yp such as 45,X male or 46,XX male [5]. The fourth type is an

Xq;Yq translocation that produces a derivative Y chromosome with a partial deletion of Yq and a

partial duplication of Xq resulting in functional distal Xq disomy such as 46,X,der(Y)t(X;Y)

(q27.3;q11.2) [6]. The fifth type is an Xp;Yq translocation that produces a derivative Y

chromosome with a partial deletion of Yq and a partial duplication of Xp resulting in functional

distal Xp disomy such as 46,X,der(Y)t(X;Y)(p22.13;q11.23) [7] and 46,X,der(Y)t(X;Y)

(p22.3;q11.2) [8]. The sixth type is an Xp;Yp translocation that produces a derivative Y

chromosome with a partial deletion of Yp and a partial duplication of Xp resulting in functional

distal Xp disomy and sex reversal such as 46,X,der(Y)t(X;Y)(p21.2;p11.3) [9]. The seventh type

is an Xq;Yp translocation that produces a derivative X chromosome with a partial deletion of Xq

and a partial duplication of Yp and hermaphrodite such as 46,X,der(X)t(X;Y)(q28;p11.31) [10].

Here, we present our experience of prenatal diagnosis and array comparative genomic

hybridization (aCGH) characterization of a de novo X;Y translocation of 46,X,der(X)t(X;Y)

(p22.31;q11.221) in a fetus with a female phenotype and short limbs on prenatal ultrasound.

A 37-year-old, gravida 3, para 1, woman underwent amniocentesis at 17 weeks of gestation

because of advanced maternal age. Her husband was 47 years old. Prenatal ultrasound at 17

weeks of gestation revealed a female fetus with a biparietal diameter (BPD) of 3.9 cm (17 weeks),

an abdominal circumference (AC) of 12.36 cm (18 weeks) and a femur length (FL) of 2.19 cm (16

weeks). Cytogenetic analysis of cultured amniocytes revealed a derivative X chromosome with an

X;Y translocation involving the p arm of the X chromosome and the q arm of the Y chromosome

(Fig. 1). The parental karyotypes were normal. Metaphase fluorescence in situ hybridization

(FISH) analysis using Xp11.1-p11.21 specific probe RP11-431N15 (56,571,162 – 56,751,665 bp)

and Y centromere specific probe DYZ3 (Vysis, Downers Grove, IL, USA) showed absence of the

Y centromere indicating that the derivative chromosome was monocentric (Fig. 2). Molecular

analysis of SRY gene revealed a negative finding in the uncultured amniocytes. The breakpoints

on Xp and Yq were precisely mapped by oligonucleotide-based aCGH CytoChip Oligo array

(BlueGnome, Cambridge, UK). The aCGH results refined the breakpoint at 8,457,738 bp on

Xp22.31 (UCSC hg18, NCBI build 36. March 2008) with an about 5.7-Mb deletion of

Xp22.31pter, and the breakpoint at 14,530,164 bp on Yq11.221 (UCSC hg18, NCBI build 36.

March 2008) with an about 12.6-Mb deletion of Yq11.221pter (Fig. 3). The fetal karyotype was

46,X,der(X)t(X;Y)(Xqterp22.31::Yq11.221qter) or 46,X,der(X)t(X;Y)(p22.31;q11.221) (Fig.

1). Prenatal ultrasound at 19 weeks of gestation revealed a BPD of 4.4 cm (19 weeks), an AC of

12.7 cm (18 weeks) and an FL of 2.5 cm (17 weeks). After genetic counseling, the parents elected

to terminate the pregnancy. A 358-g fetus was delivered at 21 weeks of gestation with body length

of 25 cm, a normal female external genitalia and shortening of the humerus and femur.

The present case had a partial duplication of Yq (Yq11.221qter) and a partial deletion of Xp

(Xp22.31pter) encompassing the genes of SHOX (OMIM 312865), ARSE (OMIM 300180),

NLGN4X, VCX3A (OMIM 300533), STS (OMIM 300747) and KAL1 (OMIM 308700). Since

Yq11.2qter does not contain the sex determining gene, the phenotype of patients with t(X;Y)

(p22;q11) depends on the Xp deletion rather than Yq duplication.

The majority of female patients with 46,X,der(X)t(X;Y)(p22;q11) are phenotypically normal

except short stature, whereas male patients with 46,Y,der(X)t(X;Y)(p22;q11) always have

phenotypic abnormalities because of nullisomy of partial Xp and may manifest, due to nullisomy

of the Xp region, short stature and dyschondrosteosis (related to SHOX), chondrodysplasia, puneta

(related to ARSE), hypogonadotropic hypogonadism with anosmia (related to KAL1) and ocular

albinism (related to OA1) [2,11-17].

Females with a microscopic or submicroscopic deletion of Xp encompassing the SHOX gene

region have been known to be associated with the Leri-Weill dyschondrosteosis (LWD, OMIM

127300). LWD is characterized by dyschondrosteosis, short stature, mesomelic shortening of the

long bones and bilateral Madelung deformity of the wrists. LWD can be caused by point

mutations or haploinsufficiency of the SHOX gene [18-21]. The SHOX gene is involved in

skeletal abnormalities and other stigmata in Turner syndrome such as short stature, cubitus valgus,

genu varum, high-arched palate, micrognathia and sensorineural deafness [22]. LWD has been

observed in patients with an X;Y translocation [14,17,23-27]. Joseph et al [28] reported prenatal

diagnosis of 46,X,der(X)t(X;Y)(p22;q11) at amniocentesis because of an elevated level of

maternal serum -fetoprotein, advanced maternal age ad a previous child with trisomy 21,

respectively in three pregnancies. In one pregnancy, Joseph et al [28] found that the limbs were at

the short end of the normal range. The present case provides evidence that short limbs can be a

second-trimester ultrasound feature of female fetuses with 46,X,der(X)t(X;Y)(p22;q11).

Acknowledgements

This work was supported by research grants NSC-99-2628-B-195-001-MY3 from the National Science Council and MMH-E-100-04 from Mackay Memorial Hospital, Taipei, Taiwan.

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Figure Legends

Fig. 1. A karyotype of 46,X,der(X)t(X;Y)(p22.31;q11.221).

Fig. 2. Metaphase fluorescence in situ hybridization analysis using Xp11.1-p11.21 specific probe RP11-431N15 (56,571,162 – 56,751,665 bp; spectrum green) and Y centromere specific probe DYZ3 (spectrum red) shows absence of the red signal on the derivative chromosome X [der(X)].

Fig. 3. Oligonucleotide-based array comparative genomic hybridization shows (A) Xp and Yp deletions (arrows) on the whole genome view and (B) a breakpoint at Xp22.3 (arrow) on X chromosome and a breakpoint at Yq11.221 on Y chromosome.