Clin Genet 2010: 78: 402–404Printed in Singapore. All rights reserved

© 2010 John Wiley & Sons A/SCLINICAL GENETICS

doi: 10.1111/j.1399-0004.2010.01437.x

Letter to the Editor

Submicroscopic familial chromosomaltranslocation between 7q and 12p mimickingan autosomal dominant holoprosencephalysyndrome

To the Editor :In 1977, Martin et al. (1) described a novel auto-

somal dominant midline cleft syndrome resem-bling familial holoprosencephaly in this journal.At the time, the genetic etiology of this syn-drome was unknown. We recently reevaluated thisfamily and identified an unbalanced chromosomaltranslocation between 7q and 12p involving SonicHedgehog (SHH ).

The proband (III-10 in the original study)was a 54-year-old man with moderate mentalretardation and congenital scoliosis. He showeddelayed development and had an intelligencequotient of 49. He had a broad nasal root andtip and a long prominent chin (Fig. 1a), but nophysical features suggestive of holoprosencephaly.Complete absence of the sacrum and coccyxbelow S3 was identified during the evaluation.Proband IV-5, a first cousin once removed of theproband III-10, was 34 years old and had globaldevelopmental delay/mental retardation. ProbandIV-5 had downslanting palpebral fissures, a broadnasal tip, and a long prominent chin (Fig. 1b). Hehad microforms of holoprosencephaly, includinga single maxillary central incisor, cleft uvula, andabsence of the superior labial frenulum (Fig. 1c,d).X-ray study identified partial vertebral agenesisbelow S1. The family history was remarkablefor the typical facial characteristics associatedwith holoprosencephaly in several relatives, all ofwhom died shortly after birth as described in theoriginal article.

To elucidate the underlying mechanism of thissyndrome, we performed microarray compara-tive genomic hybridization (CGH) analysis onIII-10 and IV-5 with Signature Select OS 105Kv1.1, using an Agilent 105K platform (SignatureGenomics, Spokane, WA). This revealed a dele-tion of the chromosomal region 7q36.2–7q36.3

(153,236,516–158,767,841) and duplication of12p13.33–12p13.31 (85,117–7,316,329) in bothprobands; both have the same unbalanced chro-mosomal translocations. The 5.53 Mb deletion at7q36 included SHH and HLXB9 genes. Within thisinterval, more than 20 genes were located. Thesize of the duplication at 12p13.3 was 7.24 Mb,and more than 80 genes were located within theduplicated segment. In addition to the unbalancedchromosomal translocation between 7q and 12p,proband IV-5 was identified to have an approxi-mately 270 kb microduplication of chromosomalregion 20q11.21 (29,341,538–29,611,708). Thismicroduplication includes about 10 genes withinthe duplicated region; however, a similar dupli-cation has never been reported. Therefore, thesignificance of this duplication is unknown. Anapparently balanced chromosomal translocationbetween 7q36 and 12p13 was identified in probandIV-5’s mother.

Terminal deletion of 7q was identified as oneof the causes of holoprosencephaly, leading tothe identification of SHH as a causative genefor holoprosencephaly (2, 3). However, patientswith 7q terminal deletion have a wide phenotypicspectrum (4). Similarly, we observed a highlyvariable expression in this family from a fulland severe holoprosencephaly phenotype to theabsence of microform findings. The analysisof a large family in which a chromosomalanomaly segregates provides a unique opportunityto eliminate the effect of gene dosage becausewe can assume that the size of the deletionis the same in all affected family members.Therefore, we conclude that the occurrence ofholoprosencephaly was not determined solely bythe size of the deletion at 7q36. Further studiesare required to identify the factors that influencethe occurrence of holoprosencephaly that result

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Letter to the Editor

a) b)

c) d)

Fig. 1. (a) Facial appearances of proband III-10, (b) facial appearances of proband IV-5, (c, d) oral phenotypes of the probandIV-5, (c) single maxillary central incisor and absence of the superior labial frenulum, and (d) cleft uvula.

from 7q36 deletions. Terminal deletions of 7qalso lead to the identification of HLXB9 geneas a causative gene for autosomal dominantsacral agenesis (5). Sacral agenesis found in bothprobands probably represents the consequence ofthe haploinsufficiency of HLXB9.

The phenotypes of our probands were also likelyto be influenced by the duplication of chromosome12p13. Our patients shared characteristic facialfeatures of 12p trisomy including a prominent noseand a pointed chin, which became more promi-nent in adulthood (6). The findings of our studyreinforce the view that there is a specific dys-morphism associated with 12p duplication, whichis particularly apparent in adulthood. Therefore,we hypothesize that the critical genomic regionresponsible for facial dysmorphism associatedwith 12p trisomy is located at 12p13.31–13.33,although co-occurrence of 7q deletion impedes aclear conclusion. Three family members died intheir infancy, presumably because of holoprosen-cephaly. Because our probands lived to adulthood,our findings confirmed those of Segel et al. (6):

12p trisomy does not usually cause significantearly mortality.

Our findings underscore the importance ofreevaluation of previously described unique cases.With advances in genetic testing modalities, forexample the routine use of array CGH in clinicalpractice, such a strategy could identify geneticbasis of other rare syndromes.

K Izumia ,b,c

D Cullera ,b

BD Solomond

M Muenked

AS Parikha ,b,c

aCenter for Human Genetics, University HospitalsCase Medical Center, Cleveland, OH, USA,

bDepartment of Genetics, Case Western ReserveUniversity, Cleveland, OH, USA,

cDepartment of Pediatrics, Rainbow Babies andChildren’s Hospital, Cleveland, OH, USA, and

dMedical Genetics Branch, National Human GenomeResearch Institute, National Institutes of Health,

Bethesda, MD, USA

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References

1. Martin AO, Perrin JC, Muir WA et al. An autosomal dominantmidline cleft syndrome resembling familial holoprosencephaly.Clin Genet 1977: 12 (2): 65–72.

2. Belloni E, Muenke M, Roessler E et al. Identification of Sonichedgehog as a candidate gene responsible for holoprosen-cephaly. Nat Genet 1996: 14 (3): 353–356.

3. Roessler E, Belloni E, Gaudenz K et al. Mutations in thehuman Sonic Hedgehog gene cause holoprosencephaly. NatGenet 1996: 14 (3): 357–360.

4. Roessler E, Ward DE, Gaudenz K et al. Cytogenetic rearrange-ments involving the loss of the Sonic Hedgehog gene at7q36 cause holoprosencephaly. Hum Genet 1997: 100 (2):172–181.

5. Ross AJ, Ruiz-Perez V, Wang Y et al. A homeobox gene,HLXB9, is the major locus for dominantly inherited sacralagenesis. Nat Genet 1998: 20 (4): 358–361.

6. Segel R, Peter I, Demmer LA et al. The natural history oftrisomy 12p. Am J Med Genet A 2006: 140 (7): 695–703.

Correspondence:Kosuke Izumi, MDCenter for Human GeneticsUniversity Hospitals Case Medical CenterClevelandOH 44106USATel.: +1 216 844 3936Fax.: +1 216 844 7497e-mail: Kosuke.Izumi@UHhospitals.org

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