Segregation of a Familial Balanced (12;10) InsertionResulting in Dup(10)(q21.2q22.1) andDel(10)(q21.2q22.1) in First Cousins

Kimberly F. Doheny,1,3* Sonja A. Rasmussen,1 Julie Rutberg,1 Gregg L. Semenza,1Judith Stamberg,4 Marcia Schwartz,5 Denise A.S. Batista,2 Gail Stetten,2 and George H. Thomas1,3

1Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland2Department of Gynecology and Obstetrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland3Genetics Department, Kennedy Krieger Institute, Baltimore, Maryland4Division of Human Genetics, School of Medicine, University of Maryland at Baltimore5Patuxent Medical Group, Columbia, Maryland

An interchromosomal insertion in 3 genera-tions of a family was ascertained throughtwo developmentally delayed first cousins.Cytogenetic analysis using G-banding andchromosome painting showed an appar-ently balanced direct insertion of chromo-some 10 material into chromosome 12,ins(12;10)(q15;q21.2q22.1), in the mothersand grandfather of these children. Theproposita inherited only the derivative 10chromosome, resulting in deletion of10q21.2 → 22.1 while her cousin inheritedonly the derivative 12, resulting in duplica-tion of 10q21.2 → 22.1. A comparison of theproposita with published deletion cases sug-gests a pattern of anomalies attributable todeletion of the 10q21 → q22 region: develop-mental delay, hypotonia, a heart murmur,telecanthus, broad nasal root and ear abnor-malities. This is the first report of a nontan-dem duplication of the 10q21 → q22 region.The phenotype of the cousin with the dupli-cation does not overlap greatly with pub-lished tandem 10q duplications. Finally, thisreport reaffirms the importance of obtain-ing family studies of patients with intersti-tial chromosomal abnormalities. Am J. Med.Genet. 69:188–193, 1997. © 1997 Wiley-Liss, Inc.

KEY WORDS: insertion; translocation; chro-mosome 10; del(10)(q21.2q22.1);

dup(10)(q21.2q22.1); partialmonosomy 10q; partial tri-somy 10q

INTRODUCTION

Most translocations arise due to exchange of termi-nal segments of chromosomes. Insertions are relativelyrare aberrations, occurring with an estimated fre-quency of less than 1 in 5,000 infants [Chudley et al.,1974]. While a few case reports of inherited interchro-mosomal insertions have been published [Abuelo et al.,1988; Bowen et al., 1983; Chudley et al., 1974; Edelhoffet al., 1991; Hegemann et al., 1996; Sawyer et al., 1994;Shaffer et al., 1993; Toomey et al., 1978; Van de Voorenet al., 1984], most have been de novo occurrences. Herewe report a 3-generation family with an interchromo-somal insertion of chromosome 10q21.2 → 22.1 mate-rial into chromosome 12. One member of this family isdeleted and another is duplicated for the region10q21.2 → 22.1 due to unbalanced segregation of theinsertion. Examination of their manifestations contrib-utes to the delineation of the phenotypes associatedwith aneusomy for chromosome 10q21.2-22.1.

SUBJECTS AND METHODS

Clinical Reports

Case 1 (IV-9). Individual IV-9 (proposita, Figures 1,2aand 2b) was referred for evaluation at age 6 monthsbecause of developmental delay. She was the 2,500 gproduct of a 37 week gestation, and an uncomplicatedpregnancy, to nonconsanguineous parents. Deliverywas via cesarean section for fetal distress. Her parents(Fig. 1) had had 2 previous spontaneous abortions at 9and 13 weeks gestation.

At age 6 months, her length was 60.1 cm (<5th cen-tile), weight was 6.26 kg (10th centile) and head cir-cumference (OFC) was 41.6 cm (25th centile). Her an-

Contract grant sponsor: NICHD Mental Retardation ResearchCenter Core Grant; Contract grant number: HD24061.

Dr. Sonja A. Rasmussen is currently at Division of Genetics,Department of Pediatrics, University of Florida College of Medi-cine, Gainesville, FL.

*Correspondence to: Kimberly F. Doheny, Ph.D., Promega Corpo-ration, 2800 Woods Hollow Road, Madison, WI 53711-5399, USA.

Received 4 April 1996; Accepted 21 June 1996

American Journal of Medical Genetics 69:188–193 (1997)

© 1997 Wiley-Liss, Inc.

terior fontanel measured 4.5 × 5.5 cm (>2SD above themean), and her occiput was flat (Figure 2b). She had amildly increased amount of nuchal skin. She had bilat-eral epicanthal folds. She was telecanthic, with an in-ner canthal distance of 2.9 cm (>97th centile) and anouter canthal distance of 7.3 cm (50–75th centile). Herphiltrum appeared long, but measured 1.4 cm (withinnormal limits) and she had a broad nasal root (Figure2a). Her ears were small, with ear length on the left of4.0 cm (3rd–25th centile) and on the right of 3.8 cm (3rdcentile). There was overfolding of the helices bilaterallywith the right being greater than the left. The earswere normally set and rotated (Fig. 2b). The cardiacexam demonstrated a regular rate and rhythm withoutmurmurs. Genitalia were normal (Tanner stage I). Shehad a deep sacral dimple, transverse palmer creasesbilaterally and mild fifth finger clinodactyly. Her sec-ond and fourth toes overlapped her other toes. The neu-rologic status was normal except for hypotonia. At 6months, she was unable to roll over or lift her headfrom a prone position. At age 14 months her weight andlength were below the 5th centile and head circumfer-ence was at the 5–10th centile. In addition, she had asoft I/VI late systolic murmur; an echocardiogram wasrecommended but has not been obtained.

Using the Peabody Scales of Motor Development, atage 20.5 months her fine motor skills showed an age-equivalence of 15 months and gross motor skills wereat 11.5–12 months. Using the Early Learning Accom-plishment Profile, her cognitive skills were at a devel-opmental age of 8 months, communication skills wereat 6 months, psychosocial skills were at 11 months, andself-help skills were at age 10 months.

Case 2 (IV-2). Individual IV-2, a maternal first cousinof the proposita (Figs. 1 and 2c), was the 2,624 g prod-uct of a full term uncomplicated pregnancy to noncon-sanguineous parents. Labor and delivery were unre-markable and there were no early medical or feedingproblems. Growth was noted to be below the 5th centile

in weight since age 6 months and below the 5th centilein height since age 2 years.

Early psychomotor development was unremarkable;she walked at one year, first words were at 8 monthsand sentences at 3 years. School problems were notedin the first grade with attention difficulties and visual-motor integration skills being particular problem ar-eas. Mild fine and gross motor delays were noted. Atage 8 years she was started on methylphenidate forattention deficit hyperactivity disorder. She was seenfor developmental testing at age 8.5 years, and theWechsler Intelligence Scale for Children-Revised(WISC-R) demonstrated a full scale IQ of 74, with averbal score of 77 and performance score of 74.

Bone age was normal on several occasions and endo-crinologic evaluation showed normal thyroid function.Chromosome analysis, performed to rule out Ullrich-Turner syndrome, showed a 46,XX karyotype with anabnormality of chromosome 12 (see below).

Examination at age 11 years showed a height of127.6 cm (<5th centile), weight of 21.1 kg (<5th centile),and OFC of 50 cm (slightly above 2SD below the mean).She had epicanthal folds and a hypoplastic malar area.Nose and palate were normal (Fig. 2c). The right pinnawas slightly prominent, but both ears were normallyplaced and formed. General systemic findings were un-remarkable. There was a Tanner stage III breast tis-sue, with Tanner stage I pubic hair. Limbs were no-table for narrow hands, thin palmar skin and hypoplas-tic hypothenar eminences bilaterally.

Cytogenetic and Molecular Studies

Peripheral blood lymphocytes were obtained and pro-cessed for chromosome analysis from individuals II-4,5,6 and 7, III-1 and 3, and IV-2,3,4 and 9. Amnioticfluid cells were cultured and analyzed for individualIV-10. Metaphase preparations were obtained essen-tially as described in Gosden [1994] except for minormodifications: MEM media was used instead of RPMI,release from synchronization with thymidine to a finalconcentration of 10−5M or BrdU to a final concentrationof 8.1 × 10−5M, reincubate for 5 hours, 10 minutes at37°C, add 100 ml colcemid for 15 minutes, hypotonictreatment for 20 minutes, pre-fix with ∼3ml fix beforecentrifugation. Metaphase spreads were G-bandedwith the Giemsa-trypsin method and stained withWright or Giemsa stain.

Libraries of chromosomes 10 and 12 (pBS10 andpBS12) were provided by J.W. Gray (University of Cali-fornia, San Francisco). The probes were labeled withbiotin-14-dATP using a BioNick labeling system (BRL)and fluorescent in situ hybridization (FISH) was per-formed according to the method described by Pinkel etal. [1986, 1988] with some modifications [Batista et al.,1994].

RESULTS

Cytogenetic studies were initially performed on theproposita (IV-9, Fig. 1) because of findings suggestiveof a chromosomal abnormality. Her mother (III-3, Fig.1) was studied due to a report of an incompletely char-acterized chromosome 12 abnormality present in both

Fig. 1. Pedigree. Solid symbol indicates unbalanced karyotype,der(10)ins(12;10)(q15;q21.2q22.1), hatched symbol indicates unbalancedkaryotype, der(12)ins(12;10)(q15;q21.2q22.1), dot in symbols indicates bal-anced insertion carriers, ins(12;10)(q15;q21.2q22.1), N in symbols indi-cates Normal karyotype, empty symbol indicates not karyotyped.

Interchromosomal Insertion of 10q21.2 → 22.1 189

Fig. 2. a: Individual IV-9, proposita with deletion of chromosome10q21.2–q22.1 at age 14 months. Note bilateral epicanthal folds, telecan-thus and broad nasal root. b: Note flat occiput and small ears with over-folded helices. c: Individual IV-2, cousin with duplication of chromosome10q21.2–q22.1 at age 11 1⁄2 years. Note relatively normal appearance.

190 Doheny et al.

her phenotypically normal sister (III-1, Fig. 1) and herniece (IV-2, Fig. 1).

An apparently balanced direct insertion of chromo-some 10 material (band q21.2 to q22.1) into chromo-some 12 at band q15 was found in the proposita’smother (III-3), 46,XX,ins(12;10) (q15;q21.2q22.1) (Fig.3). FISH painting studies with pBS10 and pBS12 sup-ported the G-band interpretation of an insertion of ma-terial from chromosome 10 into a chromosome 12.FISH with pBS12 demonstrated hybridization to onechromosome 12 along its entire length. The secondchromosome 12 had a gap of fluorescence in the middleof the long arm (Fig. 4a). At this level of resolutionthere was no evidence for any reciprocal exchange ofmaterial from the derivative chromosome 12 to the de-rivative chromosome 10. FISH with pBS10 resulted inhybridization to both chromosomes 10 with fluores-cence along their entire length. In addition, it revealeda fluorescent band on a C-group chromosome in a po-sition similar to the gap observed on one chromosome12 after FISH with pBS12 (Fig. 4b).

The proposita (IV-9) carries the derivative chromo-some 10 but not the derivative chromosome 12:46,XX,der(10)ins(12;10)(q15;q21.2q22.1)mat. This re-sults in the proposita (IV-9) being deleted for materialon the long arm of chromosome 10 from band q21.2 →q22.1. Amniotic fluid cells from the at-risk fetus (IV-10,Fig. 1) had a normal karyotype, 46,XX.

Cytogenetic studies previously performed on theproposita’s maternal cousin (IV-2, Fig. 1) because ofshort stature had demonstrated an abnormality of

chromosome 12. Her phenotypically normal mother(the proposita’s maternal aunt, III-1, Fig. 1) was origi-nally interpreted as having the same chromosome ab-normality. Reexamination of metaphase spreads fromthe proband’s aunt (III-1) and cousin (IV-2) showedthat the aunt (III-1) also carried the apparently bal-anced direct insertion: 46,XX,ins (12;10)(q15;q21.2q22.1).Her daughter (IV-2), however, had inherited the de-rivative chromosome 12 but not the derivative chromo-some 10: 46,XX,der(12)ins(12;10) (q15;q21.2q22.1)mat.Individual IV-2 thus carries a duplication of chromo-some 10 material from band q21.2 → q22.1.

Additional relatives were studied (II-4,5,6,7 and IV-3,4). The proposita’s maternal grandfather (II-6) wasfound to carry the apparently balanced direct insertion:46,XY,ins(12;10)(q15;q21.2q22.1). Her maternal uncle(III-2) has been unavailable for cytogenetic study. Hehas had 2 children who both died in infancy, reportedlydue to prematurity and sudden infant death syndrome.All other relatives studied cytogenetically had normalchromosomes (Fig. 1).

DISCUSSIONTo our knowledge, this is the first report of deletion

of 10q21.2 → 10q22.1 which has arisen through thesegregation of a balanced direct insertion. No specificsyndrome has been defined for partial monosomy 10q.The deletion patient, individual IV-9, has developmen-tal delay, hypotonia, a heart murmur, epicanthal folds,a broad nasal root, flat occiput, small abnormal ears,transverse palmar creases and abnormal positioning ofthe toes. Three previous reports have described de novodeletions for this region of chromosome 10 [Davis et al.,1982; Glover et al., 1987; Marks et al., 1991], 2 of which[Davis et al., 1982; Glover et al., 1987] give clinicaldescriptions of the index cases. The signs common to allare hypotonia, developmental delay, a broad nasal root,telecanthus and a heart murmur. The other two previ-ously described del(10)(q21q22) patients [Davis et al.,1982; Glover et al., 1987] had apparently low-set earswhich we did not observe in the proposita (IV-9).

We have identified 4 additional reports of de novointerstitial proposita deletions which overlap the re-gion of deletion in the (IV-9) [Derksen et al., 1991;Fryns et al., 1991; Ray et al., 1980; Zenger-Hain et al.,1993]. One boy with a reported 10q11.2 → q22.1 dele-tion [Zenger-Hain et al., 1993] had developmental de-lay, subaortic stenosis, hypertelorism, a flat, broad na-sal bridge, low set ears, neonatal hypotonia, frontalbossing, bright blue eyes, micrognathia, and a deepphiltrum. The patient of Ray et al., [1980] del(10)(q11q21),had developmental delay, hypotonia, heart murmur,telecanthus, plagiocephaly and large ears. Interest-ingly, a deletion of 10q11.2 → q21.1 was reported inan amniotic fluid, and subsequently found in the nor-mal mother and maternal grandmother of the fetus.The baby was reported normal at 12 weeks old [Derk-sen et al., 1991]. In the case of Fryns et al. [1991],del(10)(q11.23q21.2), the patient had the clinical diag-nosis of late-onset Cockayne’s syndrome. We propose apattern of anomalies attributable to deletion of the10q21 → q22 region as developmental delay, hypoto-nia, heart murmur, telecanthus, broad nasal root and

Fig. 3. Schematic representation and partial karyotype of chromo-somes 10 and 12 demonstrating the balanced interchromosomal insertionfound in the mother, aunt, and maternal grandfather of the proposita.Arrows indicate regions and breakpoints of interstitial deletion in chromo-some 10 and insertion of chromosome 10 material into chromosome 12.

Interchromosomal Insertion of 10q21.2 → 22.1 191

ear abnormalities. In light of the latter two reports[Derksen et al., 1991; Fryns et al., 1991], clearly fur-ther data will be necessary to define the scope and vari-ability of these manifestations.

Individual IV-2 is trisomic for chromosome 10 mate-rial from band q21.2 → 22.1 due to segregation of thebalanced insertion in her mother (III-1). All previousreports of trisomy for the proximal region of the longarm of chromosome 10 were derived from de novo di-rect duplications within chromosome 10. The duplica-tion patient has growth retardation, mild developmen-tal delay, and a few minor anomalies. There are 3 pre-vious reports of dup(10)(q21q22) [Koivisto et al., 1981;Reinthaller, 1985; Surana and Park, 1980]. The signsfound in common among all 4 individuals are fairlynon-specific: growth retardation, borderline to moder-ate mental retardation, and bilateral epicanthal folds.When compared to 3 previously reported individualswith larger duplications, dup(10)(q11q22) [De Michel-ena and Campos, 1991; Fryns et al., 1987; Vogel et al.,1978], individual IV-2 again shares only developmentaland growth retardation, minor ear abnormalities andslender hands. The patient is relatively normal (Fig.2c) and does not exhibit the craniofacial anomalies seenin other patients with duplication of the proximal seg-ment of 10q [De Michelena and Campos, 1991].

The observed phenotypic differences between the pa-tient and those previously reported could be due to as-certainment bias, position effects, differences in ge-netic background or in the exact amount of duplicatedgenetic material. Notably, individual IV-2 was karyo-typed due to short stature to rule out Ullrich-Turnersyndrome, whereas the previously reported cases werekaryotyped due to minor anomalies and developmentaldelays. Also, in the case reported here the duplicatedchromosome 10 material has been inserted into chro-mosome 12 rather than directly duplicated within chro-mosome 10.

Deletion of genetic material is thought to be more

deleterious than duplication and this family provides arare opportunity to directly compare the phenotypicconsequences of pure trisomy and monosomy for a chro-mosomal region. While neither child has major medicalproblems, the individual IV-9, who is deleted for chro-mosome 10q21.2 → 22.1, is significantly more delayedin motor and cognitive skills, and is more anomalousthan her cousin, who is duplicated for this region.

We describe a family in which a balanced insertion ofchromosome 10 material into chromosome 12 has beensegregating for at least 3 generations. In this family 3(37.5%) normal offspring, 3 (37.5%) spontaneous abor-tions, and 2 (25%) chromosomally unbalanced offspringhave occurred among 8 documented pregnancies to fe-male insertion carriers (Fig. 1). These rates do not dif-fer significantly from those seen in 7 previous multi-generational insertion reports, in which 31 (38%) nor-mal or carrier offspring, 25 (25%) spontaneousabortions, and 18 (37%) chromosomally unbalanced off-spring have occurred among 74 pregnancies to femaleinsertion carriers [Abuelo et al., 1988; Bowen et al.,1983; Chudley et al., 1974; Sawyer et al., 1994; Shafferet al., 1993; Toomey et al., 1978; Van de Vooren et al.,1984]. Fewer data are available for male insertion car-riers but among 4 previous reports describing outcomesfor 26 pregnancies, 21% were normal or carriers, 79%were chromosomally unbalanced and no losses werereported [Bowen et al., 1983; Chudley et al., 1974;Edelhoff et al., 1991; Hegemann et al., 1996]. In thecurrent family the single identified male carrier (II-6)had 2 carrier offspring; his son (III-2) has not beenavailable for study (Fig. 1).

This report demonstrates that although inherited in-sertional rearrangements are rare, they do exist, and iffound will profoundly alter the recurrence risk for afamily. Recently, interstitial microdeletions have be-gun to be studied with FISH probes, i.e. Prader-Williand Angelman syndromes [Bettio et al., 1995], Velo-cardio-facial syndrome (VCFS) [Gopal et al., 1995],

Fig. 4. FISH experiment on metaphase spreads from the proposita’s mother, a carrier of the balanced insertion, ins(12;10)(q15;q21.2q22.1).a: Chromosome 12 painting probe. A gap in hybridization signal was seen in the middle of the long arm of one chromosome 12 (arrow). b: Chromosome10 painting probe. A fluorescent band was seen on a C-group chromosome (arrow) in a position similar to the gap observed in a. A normal hybridizationpattern was seen on both chromosomes 10.

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Williams syndrome [Lowery et al., 1995], and Smith-Magenis syndrome [Zhao et al., 1995]. Missegregationof submicroscopic terminal translocations was de-scribed previously in families resulting in cases ofMiller-Dieker, Wolf-Hirschhorn, Cri-du Chat, anda-thalassemia/MR syndromes [for review see Ledbet-ter, 1992]. Thus it seems possible that submicroscopicinterstitial deletions or duplications could be derivedfrom missegregation of interchromosomal insertionsand should be identifiable with current FISH technol-ogy.

ACKNOWLEDGMENTS

We thank all of the members of the Kennedy KriegerInstitute Cytogenetics Laboratory for their technicalexpertise in the preparation of these cases, especiallyKellee McLean for the original identification of the bal-anced insertion. In addition, we thank the family forallowing the publication of clinical photographs. K.F.D.and G.H.T. are partially supported by NICHD MentalRetardation Research Center Core Grant, HD24061.

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