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Keywords:

  • imprinting;
  • 4p monosomy;
  • 11p trisomy;
  • cryptic unbalanced translocation;
  • genomic microarray

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Paternal duplications of chromosome region 11p15 can result in Beckwith–Weidemann syndrome (BWS), whereas maternal duplications of the same region on 11p15 can result in Russell–Silver syndrome (RSS). These two syndromes have numerous opposing phenotypes, especially with regards to growth parameters. The differences in the phenotype are proposed to be due to altered dosage of imprinted genes that control growth within this region of 11p15. Wolf–Hirschhorn syndrome (WHS) is due to deletions of a region in 4p16.3 and there is no known parent-of-origin effect for deletions of the WHS critical region, and no genes are known to be imprinted in this region. We report on three individuals with very similar unbalanced translocations resulting in a derivative chromosome 4 with both a deletion of 4p16.3 and a duplication of 11p15. Two of these individuals are family members with one inheriting the derivative 4 from her balanced mother and the other inheriting the derivative 4 from his balanced father. The third individual is unrelated and inherited his derivative 4 from his balanced father. While the findings of these individuals included some features of WHS and RSS or BWS, the phenotypes as an aggregate are distinct from these syndromes. The genomic and phenotypic characterization of these three individuals demonstrates how unbalanced translocations can result in the modification of chromosome duplication and deletion syndromes and identifies genomic architecture that may be responsible for mediating a recurrent translocation between 4p and 11p. © 2008 Wiley-Liss, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Wolf–Hirschhorn syndrome (WHS) is due to a hemizygous deletion of a region in 4p16.3 and is characterized by prenatal and postnatal growth delay, microcephaly, mental retardation/developmental delay, characteristic facial features and seizures [Battaglia et al., 2001]. Variable clinical features include feeding difficulties and congenital malformations such as heart malformations, renal and genitourinary tract defects, skeletal anomalies and midline defects such as coloboma, cleft lip/palate, and hypospadias. The monosomy of 4p seen in WHS can occur either as a simple deletion (occurs in the majority of cases) or as part of an unbalanced translocation (as seen in approximately 40% of cases) [South et al., 2008]. When coupled with a partial trisomy as part of an unbalanced translocation, the resulting phenotype is still primarily consistent with WHS [Wieczorek et al., 2000]; however, some alterations of the expected phenotypes can be observed [South et al., 2008].

Beckwith–Weidemann syndrome (BWS) is due to alterations involving either the methylation of specific regions on 11p15, mutation of the CDKN1C gene on 11p15, or paternal duplication of 11p15 through either uniparental disomy or an unbalanced translocation [Weksberg et al., 2005]. Russell–Silver syndrome (RSS) has also been linked to alterations of this same region on 11p15; however, these alterations involve opposing methylation patterns to those seen in BWS as well as maternal duplications of this region on 11p15 [Fisher et al., 2002; Eggermann et al., 2005, 2006; Gicquel et al., 2005; Schonherr et al., 2006, 2007]. These two syndromes also have numerous opposing phenotypes with BWS characterized by fetal macrosomia, asymmetry due to hemihyperplasia, and increased risk for embryonal tumors; whereas, RSS is characterized by prenatal and postnatal growth retardation with a relatively normal head circumference and asymmetry due to hemihypoplasia [Patton, 1988; Price et al., 1999; Weksberg et al., 2005]. These opposing phenotypes can be explained by noting the paternal imprinting pattern results in an increase in expression of genes promoting growth (as seen in BWS), whereas the maternal imprinting pattern results in an increase in expression of genes repressing growth (as seen in RSS).

We describe three patients with unbalanced translocations resulting in both a 4p partial monosomy and an 11p partial trisomy. The genomic and phenotypic characterization of these patients shows significant modification of the expected WHS phenotype by the 11p trisomy in a parent-of-origin specific manner. We discuss the possible mechanism for this cryptic recurrent translocation and the usefulness of molecular-level analyses in patients with unexplained delays and dysmorphic features.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

G-banded chromosome analysis was performed at the 550 band level using standard procedures. Fluorescence in situ hydrization (FISH) was performed using both commercially available subtelomere probes and a probe overlapping the WHSC1 gene on 4p16.3 (Vysis, Abbott Laboratories, Downers Grove, IL) using the manufacturer's protocol, and home-brewed bacterial artificial chromosome (BAC) probes. BACs used for FISH analysis were obtained from either Invitrogen Corporation (Carlsbad, CA) or Spectral Genomics Inc./PerkinElmer (Turku, Finland) and included RP11-357G3, RP11-91B20, CTD-2226C18, and RP11-120E20. The methods used to grow, label, and hybridize these BACs has been described [South et al., 2006]. Slides were viewed on an Olympus BH2 microscope and images analyzed using the Cytovision software package form Applied Imaging Corporation (San Jose, CA).

Comparative genomic hybridization (CGH) microarray analysis was performed using the SpectralChip 2600™ array platform and following the manufacturer's protocol (Spectral Genomics, a subsidiary of Perkin Elmer Corporation, Houston, TX, Spectral Genomics Inc./PerkinElmer). This platform analyses genomic copy number using BACs spaced through-out the genome at approximately 1 Mb intervals, with increased density near the telomeres. Scanning was performed with Axon's GenePix microarray scanner and analyzed using SpectralWare 2.2 for the preparation of ratio plots.

This study was approved by the University of Utah Institutional Review Board and informed consent was obtained for each family member described.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Clinical Findings

Patient 1

Patient 1 was born at 38 weeks gestation with a birth weight of 3,330 g, a length of 50.8 cm and a normal head circumference. Club feet were recognized at birth. Patient 1 had experienced early difficulties in drinking fluids, but he did not have any documented gastroesophageal reflux and did not require any tube feeding or gastronomy. He had a left brachial cleft and an umbilical hernia, both of which were repaired at 1 year of age. The bilateral club feet were repaired at 5 years of age. MRI scans of the brain at 6 months, 3 years and 9 years of age were normal.

Onset of seizures occurred at 3 years of age and patient was on anti-seizure medication with approximately two to four seizures per year. The most recent EEG at the age of 8 years was abnormal due to the presence of left central sharp wave discharges with apneic slowing in the awake state, with activation and conversion to the spike and wave in sleep, indicating a significant underlying neuronal dysfunction.

Patient 1 smiled at 6 months and sat up at 3 years. His first words were at 2 years, and at 9 years he began toilet training. At the age of 10, he was able to scoot around, but he was still unable to stand or walk with support and comprehension was at about the 6–12 month level. At the age of 10 he was followed for strabismus, scoliosis, and kyphosis. He had no history of hemihyperplasia, macroglossia, neonatal hypoglycemia, genitourinary defects, cleft lip or palate, ear pits or tags, or hearing loss. Growth velocity remained normal and at the age of 10 years, he weighed 21.7 kg and was 122 cm in height (3rd centile for both measurements).

At the age of 12 years his OFC was 52 cm, which is at the 25th centile. Physical features included curly hair, a flattened nasal tip with normal height to the nasal bridge, apparent mild hypertelorism, a short philtrum, and structurally normal ears. His facial gestalt (Fig. 1B) was not typical of WHS.

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Figure 1. Family history and facial photographs of the three patients. A: Pedigree of Patient 1 family showing extensive history of miscarriages on paternal side and that patient's father is a confirmed carrier of the balanced translocation. The patient's brother has not been tested but has a normal phenotype. B: Facial features of Patient 1 at 9 years of age. C: Pedigree of Patients 2 and 3 family showing father of Patient 3 and mother of Patient 2 are both confirmed carriers of the balanced translocation. D: Facial features of Patient 3 at 35 years of age. E: Facial features of Patient 2 at 3 years of age. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.].

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Patient 2

Patient 2 was born at 31 weeks gestation after induction due to severe intrauterine growth retardation. Birth weight was 723 g <5th centile), length was 30 cm (<5th centile) and OFC was 26.5 cm (25th centile). At birth, genetics was consulted, and the diagnosis of Russell–Silver was considered but not confirmed. She failed her newborn hearing screen and was diagnosed to have severe sensorineural loss as an infant and middle ear effusions.

Patient 2 experienced significant postnatal growth deficiency and feeding difficulties with gastroesophageal reflux that required tube feeding for the first 4 months. She had surgical repair for malrotation of intestine and PE tubes placed during these early months.

Sonograms of the heart and kidneys were normal, and ophthalmology evaluation showed no ocular defects. A CT scan at 10 months of age noted stable ventricular enlargement without hydrocephalus, extra axial subarachnoid space and normal brain parachyma. Because of her relative macrocephaly and mild ventriculomegaly on CT scans, she was followed closely by neurosurgery but never developed hydrocephalus. Seizures began at equation image years of age and at 3 years of age she remained well-controlled on anticonvulsants.

At the age of 9 months on follow-up evaluation at the Genetics clinic, her weight was 3.3 kg, her length was 52.7 cm (both far below 3rd centile) and her OFC was 44 cm (50th centile). Facial features included a prominent forehead, low nasal root, upturned nasal tip, normal philtral length and downturned corners of her mouth (Fig. 1E). Her hands showed absence of the distal crease on the 4th and 5th digits. There was 2–3 toe syndactyly and marked decrease in muscle mass and tone.

At the age of 3 years, the patient's weight and height were well below the 3rd centile, but head circumference was at the 90th centile. At equation image years of age, Patient 2 was able to smile, sit up and bottle-feed herself. However, she did not stand or walk with support and while vocalizing said no consistent words.

Patient 3

Patient 3 was evaluated in the context of his niece, Patient 2. Patient 3 was born full-term with a birth weight of 3,487 g, a length of 51 cm and a normal head circumference. He was noted to have hypospadias, which was later surgically corrected. Medical history was negative for heart defects, bladder defects, cleft lip or palate, hearing loss, or feeding difficulties. Seizures began about the age of 1 year and at 35 years of age he was still on anti-seizure medication. He developed scoliosis and was diagnosed by imaging to have a single kidney. The patient grew well during infancy and early childhood, according to his parents but fell off the growth curve in height during later childhood.

Patient 3 smiled at 3 months, sat up at 1 year, stood at 2 years and began to walk with support and then without support at 3 years of age. He began to feed himself at 2 years and was toilet trained by 4 years of age. Patient 3 could run and climb stairs at 4 years of age and began to dress himself at 5 years of age. At 35 years, he was non-verbal, but communicated through signs and gestures and cognitive abilities were between 2 and 5 years of age.

On exam at 35 years of age, weight was 47.6 kg and height was 147 cm (less than the 3rd centile for both measurements). OFC was 56 cm (50th centile). His facial features showed a high forehead, deep-set eyes, high nasal root, and bridge, short philtrum, and a relative thinness of the upper lip vermillion. Ears were mildly prominent. While showing some overlap, his appearance was not typical for an adult with WHS (Fig. 1D).

A summary of these clinical findings compared to those common to WHS, RSS, and BWS is contained in Table I.

Table I. Comparison of Clinical Features
 WHSRSSBWSPatient 1, 4p–11p+ patPatient 2, 4p–11p+ matPatient 3, 4p–11p+ pat
Prenatal growthIUGRIUGRFetal gigantism Severe IUGR 
Postnatal growthDelayed growthDelayed growth w/asymmetry due to hemihypotrophyMacrosomia w/asymmetry due to hemihyperplasiaNormal (3%)≫3%Normal
Head circumferenceMicrocephalyNormal “pseudo-hydrocephalus”MacrocephalyNormalNormal “pseudo-hydrocephalus” (88%)Normal
Mental developmentMild to severe delayNormal to mild delayUsually normal, delay if karyotype shows 11p15 duplicationSevere mental retardationDevelopmental delaySevere mental retardation
HypoglycemiaNot commonInfantileNeonatal
Renal abnormalities++Missing one kidney
Omphalocele/umbillical hernia+Umbilical hernia
Embryonal tumors+
Ear creases/pits++
Feeding difficulties+++ (due to macroglossia)±+
Cleft palate+RareRare
Prematurity++++ 
Structural cardiac anomalies++
Facial featuresHypertelorism, broad nasal bridge, prominent and broad forehead, short philtrum, micrognathia, downturned mouthTriangular face, prominent and broad forehead, micrognathiaMacroglossia, facial macrosomiaSee Figure 1BSee Figure 1ESee Figure 1D
Hearing loss++
Skeletal anomalies+Normal skeletal surveyNormal skeletal surveyBilateral club feet, scoliosis, kyphosisBasilar invaginationScoliosis
Seizures++++

Characterization of Genetic Imbalance

Patient 1 and Patient 2 were referred for routine chromosome analysis due to multiple congenital anomalies (Fig. 1B,E). Both had a normal G-banded chromosome analysis; however, subsequent subtelomere FISH studies showed that both carried a cryptic 4p subtelomere deletion and 11p subtelomere duplication due to an unbalanced translocation involving 4p and 11p. Further analysis with a FISH probe to the WHS critical region showed the 4p16.3 region was deleted due to the unbalanced translocation in both patients.

Patient 2 had an uncle (Patient 3) with a history of developmental delay and dysmorphic features (Fig. 1D). FISH using the WHS and 11p subtelomere probes was performed on this man and showed the same unbalanced translocation resulting in partial monosomy of 4p and partial trisomy of 11p.

A family history revealed recurrent miscarriages for Patient 1's parents and paternal grandparents (Fig. 1A). Chromosomes and FISH were performed in both of Patient 1's parents. The mother had both normal chromosomes and subtelomere FISH analyses for the 4p and 11p regions. Patient 1's father had a normal chromosome analysis but FISH revealed a cryptic balanced translocation involving the WHS critical region and the 11p subtelomere region. Therefore, the unbalanced translocation in Patient 1 is paternal in origin.

Since the identical unbalanced translocation was identified in Patient 2 and Patient 3, the mother of Patient 2 was presumed to carry the balanced version of this translocation (Fig. 1C), and this was confirmed using 4p and 11p FISH probes. FISH analysis further showed the maternal grandfather also carries the same balanced translocation between 4p and 11p. Therefore, the unbalanced translocation in Patient 2 is paternal in origin, and the unbalanced translocation in Patient 3 is maternal in origin.

Further characterization of the imbalance in all three patients was achieved through a combination of CGH microarray analysis and FISH with home-brewed BACs. The combination of FISH and microarray revealed identical results in all three patients with the translocation breakpoint on 4p occurred between BACs RP11-357G3 and RP11-91B20 and is between 3.39 and 4.85 Mb in size (Fig. 2A) and the translocation breakpoint on 11p occurred between BACs CTD-2226C18 and RP11-120E20 and is between 2.87 and 3.57 Mb in size (Fig. 2B). Therefore, the deletion of 4p does include both critical regions for WHS [Zollino et al., 2003; South et al., 2007] and the imprinted genes implicated in BWS [Weksberg et al., 2005] and RSS [Gicquel et al., 2005; Eggermann et al., 2006; Schonherr et al., 2006, 2007].

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Figure 2. Genomic characterization of the 4p deletion and 11p duplication. A combination of CGH microarray and FISH showed the breakpoint on 4p to fall between RP11-357G3 and RP11-91B20 in all three patients (A) and the breakpoint on 11p to fall between CTD-2226C18 and RP11-120E20 in all three patients (B). The location of the BACs analyzed and the genes and critical regions implicated in WHS, BWS, and RSS are shown as well as the location of a 115 kb low-copy repeat that falls within the breakpoints that may mediate the translocation. Not shown are other genes and low-copy repeats within these regions that are not implicated in WHS, BWS, RSS, or this rearrangement. The location of BACs, genes, and low-copy repeats was determined using the March 2006 assembly of the UCSC Genome Browser (http://www.genome.ucsc.edu).

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

The characterization of these three patients shows that identical translocations involving a 4p monosomy and an 11p trisomy can have differing phenotypes depending upon the parent of origin, most likely due to the imprinting of genes on 11p. These alterations individually can result in either WHS, BWS, or RSS. However, when present in combination, the result is a phenotype that is distinct from these syndromes.

Previous reports have concluded that unbalanced translocations involving a 4p monosomy have a phenotype that is still consistent with WHS [Wieczorek et al., 2000]. However, when paired with an 11p duplication, these three patients showed some significant modifications of the WHS phenotype, including growth and facial phenotypes, which are characteristics of WHS that clinicians often rely upon to make the diagnosis. Features of WHS that were not modified included mental retardation and seizures. Alterations to some of the expected phenotypes for WHS have also been noted in other patients with a partial 4p monosomy and partial 11p trisomy [Stevenson et al., 2004; Mikhail et al., 2007].

At the resolution studied, Patient 1 appears to have the same translocation breakpoints as those identified in Patients 2 and 3. Two previous reports of unbalanced translocations between 4p and 11p also characterized at a molecular level showed breakpoints that fall within the same region on both 4p and 11p [Russo et al., 2006; Mikhail et al., 2007]. When viewing the breakpoint regions within the UCSC Genome Browser (www.genome.ucsc.edu) it is clear that the region between 3.5 and 4.3 Mb from the terminus of 4p is very rich in low-copy repeats (LCRs). One of these LCRs at position chr4: 3,979,407-4,094,746 is 115 kb in length and is 93% identical to an LCR at position chr11: 3,375,898–3,498,471. As this LCR is present within the breakpoints on both chromosome 4 and chromosome 11, it is interesting to speculate that this LCR may mediate the formation of a recurrent cryptic translocation between these chromosomes. However, we note that we have not proven involvement of this LCR as we have not specifically shown the translocation disrupts this particular sequence of DNA. Furthermore, it is clear that LCRs do not mediate all translocations resulting in WHS [Zollino et al., 2007].

The phenotype resulting from this recurrent 4p monsomy and 11p trisomy is different enough from WHS, BWS, and RSS to make clinical suspicion of these genetic alterations unlikely. In fact, none of these three patients were considered for the diagnosis of WHS prior to the subtelomere FISH analysis. The effect imprinting has on 11p duplications is also clearly shown by identification of the same alteration in Patient 2 and Patient 3 who present with very different phenotypes. Furthermore, the unbalanced translocations are cytogenetically cryptic and required subtelomere FISH for identification. These alterations would also be identified by a CGH microarray analysis. These findings thus also emphasize the need for higher-resolution analysis of patients with a normal karyotype and idiopathic mental retardation since cryptic unbalanced translocations can result in phenotypes distinct from described microdeletion and microduplication syndromes.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

The authors wish to thank the patients and their families for participation in this study. Funding for this study was provided in part from a grant through the Primary Children's Medical Center Foundation and a grant from the Children's Health Research Center at the University of Utah.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
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