American Journal of Medical Genetics 111:405–408 (2002)

Clinical Report

Familial Reciprocal Translocation t(7;16)Associated With Maternal Uniparental Disomy7 in a Silver-Russell Patient

Jean-Michel Dupont,1* Laurence Cuisset,2 Maryse Cartigny,3 Dominique Le Tessier,1

Christian Vasseur,2 Didier Rabineau,1 and Marc Jeanpierre2

1Histologie Embryologie Cytogenetique, CHU Cochin, AP-HP-Universite Paris 5, France2Biochimie et Genetique Moleculaire, CHU Cochin, AP-HP-Universite Paris 5, France3Endocrinologie Pediatrique, Hopital Jeanne de Flandre, CHU de Lille, Lille, France

We present the case of a maternal hetero-disomyforchromosome7in thedaughterofat(7;16)(q21;q24) reciprocal translocation car-rier. The proband was referred to the hospi-tal for growth retardation and minor facialdysmorphismwithout mental retardation. Adiagnosis of Silver-Russell syndrome wassuspected. Chromosomal analysis documen-ted a 46,XX,t(7;16)(q21;q24)mat chromosomepattern. Microsatellite analysis showed anormal biparental inheritance of chromo-some 16 but a maternal heterodisomy ofchromosome 7. Occurrence of uniparentaldisomy (UPD) is a well-recognized conse-quence of chromosomal abnormalities thatincrease the rate of meiotic nondisjunction,mainly Robertsonian translocations andsupernumerary chromosomes. Although re-ciprocal translocations should, theoreti-cally, be also at increased risk of UPD,only three cases have been reported so far.However, because the association betweenuniparental disomy and reciprocal trans-location may exist with an underestimatedfrequency, prenatal diagnosis is recom-mended when clinically relevant chromo-somes for UPD are involved.� 2002 Wiley-Liss, Inc.

KEY WORDS: uniparental disomy; reci-procal translocation; Silver-Russell syndrome; chromo-somal rearrangement

INTRODUCTION

Uniparental disomy (UPD) is the inheritance of bothhomologs of a pair from only one parent. Transmissionof the two chromosomes of the parental pair may leadto heterodisomy, whereas isodisomy results from thepresence of two copies of one chromosome. Engeldiscussed the theoretical aspects of this phenomenonin 1980 [Engel, 1980], but the first cases were ascer-tained several years later [Spenceet al., 1988;Voss et al.,1989]. Clinical consequences include autosomal reces-sive diseases and imprinting disorders [Engel, 1995,1997]. Genomic imprinting is a mammalian epigeneticmodification of the DNA leading to the expression of agene according to theparental origin of the chromosome.UPD has been reported for every chromosomal pairexcept for chomosomes 12 and 19, but clinical con-sequences have only been observed for chromosomes2, 6, 7, 11, 14, 15, and 16 [Ledbetter and Engel, 1995].Maternal UPD (7) has been detected in 10% of patientswith Silver-Russell syndrome (SRS, MIM 180860) orprimordial growth retardation [Kotzot et al., 1995;Eggermann et al., 1997] and UPD (16) has been asso-ciated with intrauterine growth retardation (IUGR)[Kalousek and Barrett, 1994].

Three mechanisms can lead to UPD (Fig. 1): trisomyrescue, monosomy rescue, and gamete complementa-tion, all resulting froman initial nondisjunctional event.Hence, every chromosomal abnormality that increasesthe occurrence of nondisjunction, such as Robertsonianand reciprocal translocations or supernumerarymarkerchromosomes, was postulated to increase the risk ofUPD. However, few cases of UPD associated with fami-lial Robertsonian translocations have been reported so

*Correspondence to: Dr. J.-M. Dupont, Histologie EmbryologieCytogenetique, Hopital Cochin, 123 Bd Port Royal, F-75014 Paris,France. E-mail: jean-michel.dupont@cch.ap-hop-paris.fr

Received 22 February 2001; Accepted 14 April 2002

DOI 10.1002/ajmg.10570

� 2002 Wiley-Liss, Inc.

far, and to our knowledge, only three cases have beenfound associated with a reciprocal translocation.

We report here on a patient with a t(7;16)matreciprocal translocation associated with a matUPD(7)and discuss the consequences for prenatal diagnosis.

CLINICAL REPORT

The proband was the seventh and last child of thefamily. Shewas delivered at 33weeks gestation after anuneventful pregnancy. IUGR was recognized at birth,with a birth weight of 1950 g (�1 SD), a height of 42 cm(�3.2 SD), and head circumference of 33 cm. Dysmor-phic features were noted (Fig. 2), including prominentforehead, low set ears, triangular face, and clinodactylyof the fifth finger. Development during infancy wascharacterized by growth retardation with very poorresponse togrowthhormonetherapy (120cmand20.3kgat 12), normal pubertal evolution, and absence ofmentalretardation. SRS was suspected.

RHG and GTG banding of the patient’s metaphasesrevealed a balanced translocation t(7;16)(q21;q24).

Karyotyping of both parents showed that the transloca-tion was maternally inherited. Fluorescence in situhybridization (FISH) studies using a 17q subtelomericprobe (Appligene-Oncor, Illkirch, France) failed toreveal any chromosomal rearrangement of this regionin our proband (data not shown).

The absence of paternal contribution at D7S495and the presence of both maternal alleles at D7S640,D7S495, and D7S504 revealed a maternal heterodi-somy 7, probably through meiosis II nondisjunction, assuggested by patient homozygozity at D7S684. Bipar-ental inheritance for chromosome 16 was ascertainedwith one informative marker (Table I).

DISCUSSION

We report on a girl suspected of SRS whose karyotyperevealed an apparently balanced t(7;16)(q21;q24)matreciprocal translocation associated with a maternalheterodisomy 7. SRS is a developmental disorder char-acterized by IUGR, short stature with asymmetry, andfacial dysmorphism [Price et al., 1999]. Themaingenetic

Fig. 1. Mechanisms of uniparental disomy in reciprocal translocationcarriers. In this example, a meiotic nondisjunction results in disomic (I andII) andmonosomic (III) gametes. In thefirst situation, after fertilizationwitha normal spermatozoid, the resulting trisomic conceptus is rescued byrandom loss of one chromosome. In one third of cases, a heterodisomy willappear. In the second situation, a nullisomic spermatozoid fertilizes the

disomic oocyte. This gamete complementation hypothesis, although lesslikely, has already been observed [Park et al., 1998]. Monosomy rescuecorresponds to the fertilization of a nullisomic oocyte with a normal sperm.This results in a monosomic conceptus that can be rescued throughduplication of the lone chromosome, leading in every case to isodisomy.

406 Dupont et al.

mechanism of this condition is not currently known, butseveral candidate loci havebeen identified.The terminalregion of the long arm of chromosome 17 was initiallyproposed because of the finding of breakpoints in 17q25in two independant SRS patients [Ramirez-Duenaset al., 1992;Midro et al., 1993]. These observations wererecently strengthened by the report of Eggermann et al.[1998] on a SRS patient with a deletion in the growthhormone gene cluster localized in 17q22–q24. In ourcase, however, chromosome banding and FISH failed toreveal any chromosomal abnormality of this region inthe patient.

A second candidate region for SRS with several im-printed candidate genes has been recognized on chromo-some 7 [Cuisset et al., 1997; Kobayashi et al., 1997;Miyoshi et al., 1998; Wakeling et al., 1998, 2000; Joyce

et al., 1999; Yoshihashi et al., 2000] and is strongly sup-ported by thefinding ofmatUPD(7) in about 10%of cases[Kotzot et al., 1995; Eggermann et al., 1997]. Analysesof several microsatellites on chromosome 7 showed amatUPD(7) in our patient, therefore strengthening theclinical diagnosis of SRS.

As hypothesized by Engel [1980], UPD may arisefollowing correction of amalsegregation, either by loss ofa supernumerary chromosome following a meiosis ormitotic nondisjunction (trisomy rescue), or by fertiliza-tion of a disomic gamete by a nullisomic one (gametecomplementation) or by duplication of a unique chromo-some (monosomy rescue) (Fig. 2).

The first two mechanisms produce a heterodisomy,and therefore both could have arisen in the present case.Trisomy rescue hypothesis is the most likely becauseit requires only one nondisjunctional event duringgametogenesis, whereas gamete complementation hasto combine two events, one during maternal meiosis I(leading to a disomic oocyte) and one during paternalmeiosis (resulting in a nullisomic spermatozoid) fol-lowed by fertilizationwith these two abnormal gametes.On the other hand, monosomy rescue leading in everycase to isodisomy could not have occurred in our patient.

The frequency of these rescuing events seems to bevery low. Most of the published cases involved Robert-sonian translocation carriers, with an estimated risk ofless than 1% of having an affected offspring [Berendet al., 2000]. In reciprocal translocation carriers, onlythree UPD affected offsprings have been reported[Smeets et al., 1992; Smith et al., 1994; Park et al.,1998], suggesting that uniparental disomy is not

Fig. 2. Proband at 10 years old.

TABLE I. Chromosomes 7 and 16 Microsatellite Analyses

Propositus Father Mother Localization

Chromosome 7D7S484 a/a a/b a/a 7p14.2D7S504 a/b a/a a/b 7q32.1D7S640 b/c a/c b/c 7q33D7S509 a/a a/a a/a 7q33D7S495 b/d a/c b/d 7q34D7S684 a/a a/b a/b 7q34

Chromosome 16D16S283 b/b a/b b/b 16p13.3AFM 361te9 a/a a/a a/a 16p13.3AFM ef34 a/a a/c a/b 16p13.3AFM a353yhl a/b a/b a/a 16p13.3AFM b070yg5 a/b b/c a/a 16p13.3

matUPD(7) in a Reciprocal Translocation Carrier 407

frequently associated with such chromosomal abnorm-alities. In accordance with this idea, the sole systematicstudydidnot showanyUPDamong theaffected childrenof 37 reciprocal translocation carriers [James et al.,1994]. However, this phenomenon might be under-estimated due to the absence of clinical consequencesof most chromosomal UPD and the lack of systematicmolecular investigations.

Therefore, regulation mechanisms that may lead toUPD during early zygote development constitute anew cause of concern during prenatal diagnosis whenchromosomes relevant for UPD are involved. Thosesituations include mainly mosaic trisomy (true fetalmosaicism or confined placental mosaicism), super-numerarymarker chromosomes, and familial or de novoRobertsonian translocations. In such instances, currentprenatal diagnosis procedures usually include mole-cular diagnosis of UPD. Practical attitude in case ofreciprocal translocation is less straightforward becauseof a lower risk of UPD.Nevertheless, the parents shouldbe informed of the possible occurrence of UPD and beoffered the opportunity of prenatal molecular testing.

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