Human Molecular Genetics, Vol. 1, No. 4
© 1992 Oxford University Press
221-227
MINI-REVIEW Deletions and translocations involving the distal short arm of the human X chromosome: review and hypotheses Andrea Ballabio* and Generoso Andria1 Institute for Molecular Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA and 1 Department of Pediatrics, University of Naples, Via S. Pansini 5, 80131 Naples, Italy Received February 4, 1992; Revised and Accepted May 26, 1992
In this review we describe the various types of chromosomal abnormalities found in the distal short arm of the human X chromosome and the most common clinical features associated with each type, emphasizing the underlying molecular mechanisms. The study of these patients has significant implications for identifying the disease genes involved. INTRODUCTION The X chromosome is currently among the best characterized among all human chromosomes'. With the exception of genes located in the pseudoautosomal region2, and a few others which have active copies on both the X and Y chromosomes, most genes on the X chromosome display a haploid status in males. As a consequence, recessive mutations in X-linked disease genes result in hemizygous affected males and heterozygous, and usually asymptomatic, carrier females. The easily-recognizable inheritance pattern of X-linked diseases allows the instant assignment of the corresponding genes to the X chromosome, narrowing down their position from anywhere in 3,000 Mb, which is the size of the human genome, to 150 Mb, the size of the human X chromosome. Furthermore, the haploid status of the X chromosome in males simplifies the analysis with genetic markers. Deletions on the X result in nullisomy in males which can be easily identified using common techniques such as Southern blotting or polymerase chain reaction (PCR). For all these reasons genetic analysis and mapping have been greatly facilitated on the X chromosome. The distal short arm of the X chromosome is a fascinating region of the human genome having some very peculiar features. It shares homology with both the short and the long arm of the Y chromosome, it contains genes escaping X-inactivation, it is not conserved in the mouse, and it shows a very high frequency of chromosomal rearrangements. The most distal part of this region (from Xpter to locus DX143) has been accurately mapped by both long range restriction analysis3 and by linkage analysis4. According to these studies, the size of this region is approximately 10 Mb and 15 cM in the physical and the genetic maps, respectively3-4. The presence of numerous patients with deletions and translocations has been of considerable help for the mapping of • To whom correspondence should be addressed
X-linked disease genes in this region. An accurate phenotype / genotype correlation in these cases can lead to both the identification of disease genes and the understanding of the pathogenetic mechanisms involved in the disease phenotype. In this review we emphasize both the clinical and molecular skills that should be used jointly in the evaluation of these patients. Cytogenetic abnormalities Distal Xp rearrangements include 5 types of abnormalities: interstitial deletions, terminal deletions, X7Y translocations, X/autosomal translocations and Xp duplications. Duplications will not be discussed in this review. Interstitial deletions. Interstitial deletions, usually not detectable by chromosome analysis, are the most common type of abnormality found in the Xp22-pter region. In the large majority of the patients these deletions involve a region of approximately 2 Mb5 including the steroid sulfatase (STS) locus and resulting in isolated X-linked ichthyosis (XLT)6"12. In some instances the deletion is not limited to the STS locus but also involves adjacent disease genes, causing contiguous gene syndromes13"15. There has been a single case report of an interstitial deletion involving Xp22.3 in a patient with short stature associated with X-linked recessive chondrodysplasia punctata16 in whom the STS locus was not deleted. Terminal deletions. Terminal deletions are usually detected both by cytogenetic and molecular analysis17"24. The name 'terminal deletion' may not be used in a strict sense in these cases, since the deleted Xp arm presumably retains a functional telomere, which may or may not correspond to the normal Xp telomere. However, chromosomes in which Xp subtelomeric markers are deleted are usually referred to as terminal deletions. The position of the breakpoints in the various patients with terminal deletions, and consequently the sizes of the deleted regions, are very variable (anywhere from 3 to 15 Mb). Therefore, the complexity of the phenotype of these patients is also variable and depends on both the number of disease genes involved and the sex of the affected individual. In male individuals nullisomy for a 'recessive' trait would result in a phenotype, whereas in females a phenotype would only be evident if the deletion has resulted in monosomy for a 'dominant' trait (see below).
Downloaded from http://hmg.oxfordjournals.org/ at Michigan State University on January 23, 2015
ABSTRACT
222 Human Molecular Genetics, Vol. I, No. 4
X/autosomal translocations. X/autosomal translocations with an Xp22 breakpoint have been found only in a few cases42"45. In balanced translocations the phenotype is presumed to be due to the disruption of a putative disease gene on the X chromosome at the site of the translocation breakpoint. However, the presence of a complex (translocation-deletion) rearrangement or a positional effect of gene dosage (or interactive gene effects) cannot be ruled out in X/autosomal translocations. In unbalanced translocations the phenotype is due to both the hemizygosity of the distal Xp region in affected females and to the trisomy of the autosomal region involved in the translocation. However, spreading of X-inactivation into the autosome, and preferential survival of cells with the normal X active, could prevent the effects of the trisomy. Most of the described patients with these abnormalities are females with X-linked dominant disorders. Molecular basis of distal Xp rearrangements The most common molecular mechanisms underlying Xp22 abnormalities are listed in table 1. Two families of low copy number repeats, the G1.3 (DXF22S) and the CRI-S232 (DXF30S) families have been mapped to Xp22.3 and several units of these repeats have been found to be clustered on either side of the STS gene, suggesting that the frequent occurrence of interstitial deletions in this region is due, at least in part, to Table I. Common molecular mechanisms of distal Xp abnormalities ABNORMALITY
MECHANISM
Interstitial deletions
Homologous recombination (unequal crossing over) between elements of > family of repeals clustered in Xp22J
X/Y translocations
Homologous recombination between regions of the X and Y chromosomes sharing high sequence identity (Xpter/Ypter or Xp22J/Yql 12)
X/autosomal translocations
Unknown
Terminal deletions
Unknown
abnormal pairing and homologous recombination between different repeat units 46 . This hypothesis was formally demonstrated by the finding of CRI-S232 repeat units at the deletion breakpoints of the majority of patients with STS deficiency5. The deletion breakpoint in a patient with a partial deletion of the STS gene has also been cloned and sequenced and a three bp homology was found at the site of the breakpoint47. Recently, we have identified a patient with Kallmann syndrome having a 3 Kb intragenic deletion within the KALIG-1 gene48, thus providing formal evidence that KALIG-149 (ADMLX50) is the Kallmann syndrome gene. Sequencing of the junction fragment from this patient revealed a 6 bp homology (CAAATT) at the deletion breakpoints. These short stretches of sequence homology have been suggested to facilitate end-joining reactions in nonhomologous recombination events in several regions of the genome5152. Of interest also is the observation that the deletion in the KALIG-1 gene includes the penultimate exon that encodes for one of the previously characterized neural cell adhesion homology domains (domain C in ref.26). In Xp/Yp translocations, erroneous interchromosomal recombination occurs as a result of the pairing occurring between the X and the Y pseudoautosomal regions during male meiosis. In one case, an Alu-Alu recombination event was observed25. These abnormal exchanges cause either loss or gain of the TDF gene, leading to sex reversed individuals. In Xp/Yq translocations, abnormal pairing and exchange between two highly homologous regions on Xp22.3 and Yql 1.2 takes place. The result is the translocation of Yql 1.2-qter onto distal Xp with a production of a concomitant terminal Xp22.3-pter deletion. Yen et al. recently sequenced the translocation breakpoint from another X/Y translocation patient and demonstrated the occurrence of a precise homologous recombination event between Xp and Yq41. Recently, we studied 4 unrelated X/Y translocation patients with Kallmann syndrome and found that the X and Y breakpoints are located within the Kallmann syndrome gene and its Y-linked homologue, respectively (A.B. unpublished data). Sequence analysis in one of these translocations demonstrated that the breakpoint was located within a region of >90% X-Y identity and, more precisely, within a stretch of 13 bp of complete identity. In this patient with Kallmann syndrome the translocation event created a recombinant Kallmann syndrome fusion gene retaining the entire X-linked gene, with the exception of the last exon which was Y-derived, suggesting that the 3' portion of the Kallmann syndrome gene is essential for its function and cannot be substituted by the Y-derived homologous region53. These data indicate that abnormal pairing and homologous recombination occur between Xp22.3 and Yql 1.2, as previously hypothesized35. It could be predicted that this distinctive mechanism plays an important role in the majority of X/Y translocations involving the X short arm, although other mechanisms, such as non homologous recombination, may also be involved. No information is available about the molecular mechanisms underlying X/autosomal translocation involving the distal short arm of the X chromosome. Bodrug et al. studied three X/autosomal translocations involving other regions of the X chromosome and found that these were the result of non homologous recombination with minor additions or deletions at the junction point54-55. The breakpoints of terminal deletions involving the X
Downloaded from http://hmg.oxfordjournals.org/ at Michigan State University on January 23, 2015
X/Y translocations. X/Y translocations involving the distal short arm of the X chromosome can be divided into two major groups: Xp/Yp and Xp/Yq translocations. Xp/Yp translocations involving the testis determining factor (TDF) are found in sex reversed individuals (XX males or more rarely XY females)25 - 2 8 . Usually the translocation is not visible by cytogenetic analysis and can only be detected using molecular probes. Xp/Yq translocations29"41 (for references prior to 1985 see review by Bernstein R. and references therein29) have been easily recognized cytogenetically because of the presence of the highly fluorescent Y heterochromatic region (Yql 1-qter) located at the top of the distal Xp region. Both types of translocation events cause a terminal Xp deletion. Therefore, as in 'pure' terminal deletions, the length of the deleted region and the complexity of the phenotype depend on both the position of the breakpoint on the X chromosome and on the sex of the affected individual.
Human Molecular Genetics, Vol. 1, No. 4 223 chromosome have not yet been characterized. Recent studies of a patient with a terminal deletion of chromosome 16 associated with alpha thalassemia demonstrated that the loss of the telomere was stabilized by the addition of telomeric repeats (TTAGGG) at a specific recognition site for human telomerase56'57. It will be interesting to determine if this, or other mechanisms, are involved in Xp terminal deletions.
Clinical features I SS I CDPX | MRX | XLI | KAL |
Interstitial deletions
Terminal deletions, X/Y translocations -20 -10
Figure 1. ClinkaJ features of male patients with Xp22 deletions and translocations. SS = short stature, CDPX = X-linked recessive chondrodysplasia punctata, MRX = mental retardation, XLI = X-linked ichthyosis, KAL = X-linked Kallmann syndrome. Bold lines indicate presence of a disease phenotype. Numbers besides the bold lines indicate the approximate number of unrelated patients observed in whom the chromosomal rearrangement was demonstrated either by cytogenetic or molecular analysis.
Downloaded from http://hmg.oxfordjournals.org/ at Michigan State University on January 23, 2015
Clinical findings Male patients with deletions in Xp22.3 are nullisomic for this region and consequently they show contiguous gene syndromes characterized by different combinations of phenotypes according to the length of the deletion14 (see figure 1). These contiguous gene syndromes are characterized by the association of up to five of the following diseases (see ref. 1): short stature (SS;MIM312865), X-linked recessive chondrodysplasia punctata (CDPX; MIM3O295O), mental retardation (MRX; MIM309530), X-linked ichthyosis (XLJ; MIM3O81OO) due to STS deficiency and Kallmann syndrome (KAL; MIM30870O). The phenotype can be predicted in each patient from the results of molecular analysis. Figure 1 shows the variety of phenotypes which have been observed. In addition to these phenotypes, Schnur et al. reported a family in which several male members were affected by X-linked ichthyosis associated with ocular albinism type 1 (OA1; MIM3OO5OO) in which they demonstrated a deletion of the STS gene58. They hypothesized the presence of a contiguous gene syndrome involving both the STS and the OA1 genes. However, this hypothesis is not compatible with the absence of OA1 in patients with contiguous gene syndromes involving the STS and KAL genes, suggesting that the patients reported by Schnur et al. might have a complex rearrangement. Two independent linkage studies on families with OA1 have recently been published59*. They both support the assignment of OA1 to the Xp22.3 region, although they contain conflicting data about the relative order of OA1 with respect to the other loci in the region.
Female patients with terminal Xp deletions, X/Y translocations or X/autosomal translocations typically do not show any of the recessive diseases described in affected males because of the presence of a normal X chromosome. However, they almost invariably show short stature. This observation is consistent with the presence of a gene affecting height in the pseudoautosomal region, two active copies of which are needed for normal growth (MIM312865) 14-37. Recently, there have been several reports of female patients with terminal deletions and translocations involving the Xp22 region. These patients and their clinical features are listed in Table 2. Several of these patients share clinical features which are found in two Mendelian disorders, Aicardi syndrome (AIC; MIM3O4O5O) and Goltz syndrome (Focal Dermal Hypoplasia) (FDH; MIM305600). Aicardi syndrome, first reported by Aicardi et al.61, is defined by the occurrence of all of the following features: infantile spasms, agenesis of the corpus callosum and specific chorioretinal abnormalities called 'lacunae'. A recent study of 18 cases with Aicardi syndrome summarizes the spectrum of clinical manifestations of this disease62. Ophthalmologic findings may include punched-out chorioretinal 'lacunae' (areas of depigmentation of the retinal epithelium), microphthalmia, optic nerve coloboma, nystagmus and detached retina. Costovertebral defects have been observed in several cases. Although the pathogenesis of Aicardi syndrome is unknown, neuropathological findings suggest the presence of a neuronal migration defect involving several areas of the brain63. Goltz syndrome, also known as focal dermal hypoplasia, is characterized by typical cutaneous abnormalities almost invariably present from birth (see ref. 64 and 65 for review). These are areas of aplastic skin with a linear and asymmetric distribution, they can be hypo- or hyperpigmented, and can be found in any part of the body. Common findings in Goltz syndrome include microphthalmia, chorioretinal colobomata, sparse and brittle hair, nail dystrophy, oral and dental anomalies, and various types of skeletal abnormalities, as well as a wide spectrum of digital malformations. The pathogenesis of Goltz syndrome is also unknown. The multisystemic and congenital nature of the disease and the histological findings upon analysis of the skin lesions suggest the presence of a multiple field defect resulting from a complex developmental abnormality of the connective tissue65. Some of the patients listed in Table 2 have been diagnosed as Goltz syndrome and some as Aicardi syndrome. In two patients, the presence of a contiguous gene syndrome, involving both disease genes, was hypothesized24. In other cases, the phenotype showed some similarities with either Aicardi or Goltz syndromes, although the authors stated that the criteria to make such diagnoses were not met. We think that the clinical diagnosis of these syndromes generally follows very strict criteria that do not take into account clinical variability66-67. The definition of the clinical presentation of these syndromes is therefore biased because patients with 'incomplete' phenotypes are excluded. If patients identified with a different approach (i.e. cytogenetic) are included, then the spectrum of manifestations of a particular syndrome may broaden, consequently affecting the diagnostic criteria. An alternative explanation for the differences between the patients listed in Table 2 and the patients with 'classical' Aicardi and Goltz syndromes is the presence of genetic heterogeneity for these two diseases. However, in this case one would have to postulate two forms of these diseases, both with an X-linked 'dominant' inheritance pattern.
224 Human Molecular Genetics, Vol. 1, No. 4 Table 2. Clinical features of some female* patients with Xp22 deletions and translocations AICARDI SYNDROME
GOLTZ SYNDROME z
REFERENCE
Tenninal deletion (Xp22.31-pter)
2. Temple etal. 20
Terminal deletion (Xp22.2-pter)
3. AUansonelaJ.21 (case 1)
TenranaJ deletion (Xp22.2-pter)
4.Thie»«aL23
Tenrunal deletion (Xp22.3-pter)
5. Nantomj et al. 24 (caiel)
Terminal deletion (Xp22.3-pter)
6. Naritomietal. 24 (case 2)
Terminal deletion (Xp22.3-pter)
7. Magenii E (p.c.)
Terminal deletion (Xp22.2-pter)
Z
32
X/Y translocation (Xp22/Yq 11)
9. Al GazaJi el al.36 (caje 1)
X/Y translocation (Xp22.3/Yql 1.2)
3
10. Al Gazali el al * (ca>c 2)
X/Y translocalion (Xp22.3/Yq 11.2)
11. Hulten M. (p.c.)
X/Y translocalion (Xp22/Yp)
12. Ropers et al. 42
Balanced translocation"* (Xp22.2/3ql2)
13. Piombo et al. 43
Unbalanced translocation (Xp22. l/4
© 1992 Oxford University Press
221-227
MINI-REVIEW Deletions and translocations involving the distal short arm of the human X chromosome: review and hypotheses Andrea Ballabio* and Generoso Andria1 Institute for Molecular Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA and 1 Department of Pediatrics, University of Naples, Via S. Pansini 5, 80131 Naples, Italy Received February 4, 1992; Revised and Accepted May 26, 1992
In this review we describe the various types of chromosomal abnormalities found in the distal short arm of the human X chromosome and the most common clinical features associated with each type, emphasizing the underlying molecular mechanisms. The study of these patients has significant implications for identifying the disease genes involved. INTRODUCTION The X chromosome is currently among the best characterized among all human chromosomes'. With the exception of genes located in the pseudoautosomal region2, and a few others which have active copies on both the X and Y chromosomes, most genes on the X chromosome display a haploid status in males. As a consequence, recessive mutations in X-linked disease genes result in hemizygous affected males and heterozygous, and usually asymptomatic, carrier females. The easily-recognizable inheritance pattern of X-linked diseases allows the instant assignment of the corresponding genes to the X chromosome, narrowing down their position from anywhere in 3,000 Mb, which is the size of the human genome, to 150 Mb, the size of the human X chromosome. Furthermore, the haploid status of the X chromosome in males simplifies the analysis with genetic markers. Deletions on the X result in nullisomy in males which can be easily identified using common techniques such as Southern blotting or polymerase chain reaction (PCR). For all these reasons genetic analysis and mapping have been greatly facilitated on the X chromosome. The distal short arm of the X chromosome is a fascinating region of the human genome having some very peculiar features. It shares homology with both the short and the long arm of the Y chromosome, it contains genes escaping X-inactivation, it is not conserved in the mouse, and it shows a very high frequency of chromosomal rearrangements. The most distal part of this region (from Xpter to locus DX143) has been accurately mapped by both long range restriction analysis3 and by linkage analysis4. According to these studies, the size of this region is approximately 10 Mb and 15 cM in the physical and the genetic maps, respectively3-4. The presence of numerous patients with deletions and translocations has been of considerable help for the mapping of • To whom correspondence should be addressed
X-linked disease genes in this region. An accurate phenotype / genotype correlation in these cases can lead to both the identification of disease genes and the understanding of the pathogenetic mechanisms involved in the disease phenotype. In this review we emphasize both the clinical and molecular skills that should be used jointly in the evaluation of these patients. Cytogenetic abnormalities Distal Xp rearrangements include 5 types of abnormalities: interstitial deletions, terminal deletions, X7Y translocations, X/autosomal translocations and Xp duplications. Duplications will not be discussed in this review. Interstitial deletions. Interstitial deletions, usually not detectable by chromosome analysis, are the most common type of abnormality found in the Xp22-pter region. In the large majority of the patients these deletions involve a region of approximately 2 Mb5 including the steroid sulfatase (STS) locus and resulting in isolated X-linked ichthyosis (XLT)6"12. In some instances the deletion is not limited to the STS locus but also involves adjacent disease genes, causing contiguous gene syndromes13"15. There has been a single case report of an interstitial deletion involving Xp22.3 in a patient with short stature associated with X-linked recessive chondrodysplasia punctata16 in whom the STS locus was not deleted. Terminal deletions. Terminal deletions are usually detected both by cytogenetic and molecular analysis17"24. The name 'terminal deletion' may not be used in a strict sense in these cases, since the deleted Xp arm presumably retains a functional telomere, which may or may not correspond to the normal Xp telomere. However, chromosomes in which Xp subtelomeric markers are deleted are usually referred to as terminal deletions. The position of the breakpoints in the various patients with terminal deletions, and consequently the sizes of the deleted regions, are very variable (anywhere from 3 to 15 Mb). Therefore, the complexity of the phenotype of these patients is also variable and depends on both the number of disease genes involved and the sex of the affected individual. In male individuals nullisomy for a 'recessive' trait would result in a phenotype, whereas in females a phenotype would only be evident if the deletion has resulted in monosomy for a 'dominant' trait (see below).
Downloaded from http://hmg.oxfordjournals.org/ at Michigan State University on January 23, 2015
ABSTRACT
222 Human Molecular Genetics, Vol. I, No. 4
X/autosomal translocations. X/autosomal translocations with an Xp22 breakpoint have been found only in a few cases42"45. In balanced translocations the phenotype is presumed to be due to the disruption of a putative disease gene on the X chromosome at the site of the translocation breakpoint. However, the presence of a complex (translocation-deletion) rearrangement or a positional effect of gene dosage (or interactive gene effects) cannot be ruled out in X/autosomal translocations. In unbalanced translocations the phenotype is due to both the hemizygosity of the distal Xp region in affected females and to the trisomy of the autosomal region involved in the translocation. However, spreading of X-inactivation into the autosome, and preferential survival of cells with the normal X active, could prevent the effects of the trisomy. Most of the described patients with these abnormalities are females with X-linked dominant disorders. Molecular basis of distal Xp rearrangements The most common molecular mechanisms underlying Xp22 abnormalities are listed in table 1. Two families of low copy number repeats, the G1.3 (DXF22S) and the CRI-S232 (DXF30S) families have been mapped to Xp22.3 and several units of these repeats have been found to be clustered on either side of the STS gene, suggesting that the frequent occurrence of interstitial deletions in this region is due, at least in part, to Table I. Common molecular mechanisms of distal Xp abnormalities ABNORMALITY
MECHANISM
Interstitial deletions
Homologous recombination (unequal crossing over) between elements of > family of repeals clustered in Xp22J
X/Y translocations
Homologous recombination between regions of the X and Y chromosomes sharing high sequence identity (Xpter/Ypter or Xp22J/Yql 12)
X/autosomal translocations
Unknown
Terminal deletions
Unknown
abnormal pairing and homologous recombination between different repeat units 46 . This hypothesis was formally demonstrated by the finding of CRI-S232 repeat units at the deletion breakpoints of the majority of patients with STS deficiency5. The deletion breakpoint in a patient with a partial deletion of the STS gene has also been cloned and sequenced and a three bp homology was found at the site of the breakpoint47. Recently, we have identified a patient with Kallmann syndrome having a 3 Kb intragenic deletion within the KALIG-1 gene48, thus providing formal evidence that KALIG-149 (ADMLX50) is the Kallmann syndrome gene. Sequencing of the junction fragment from this patient revealed a 6 bp homology (CAAATT) at the deletion breakpoints. These short stretches of sequence homology have been suggested to facilitate end-joining reactions in nonhomologous recombination events in several regions of the genome5152. Of interest also is the observation that the deletion in the KALIG-1 gene includes the penultimate exon that encodes for one of the previously characterized neural cell adhesion homology domains (domain C in ref.26). In Xp/Yp translocations, erroneous interchromosomal recombination occurs as a result of the pairing occurring between the X and the Y pseudoautosomal regions during male meiosis. In one case, an Alu-Alu recombination event was observed25. These abnormal exchanges cause either loss or gain of the TDF gene, leading to sex reversed individuals. In Xp/Yq translocations, abnormal pairing and exchange between two highly homologous regions on Xp22.3 and Yql 1.2 takes place. The result is the translocation of Yql 1.2-qter onto distal Xp with a production of a concomitant terminal Xp22.3-pter deletion. Yen et al. recently sequenced the translocation breakpoint from another X/Y translocation patient and demonstrated the occurrence of a precise homologous recombination event between Xp and Yq41. Recently, we studied 4 unrelated X/Y translocation patients with Kallmann syndrome and found that the X and Y breakpoints are located within the Kallmann syndrome gene and its Y-linked homologue, respectively (A.B. unpublished data). Sequence analysis in one of these translocations demonstrated that the breakpoint was located within a region of >90% X-Y identity and, more precisely, within a stretch of 13 bp of complete identity. In this patient with Kallmann syndrome the translocation event created a recombinant Kallmann syndrome fusion gene retaining the entire X-linked gene, with the exception of the last exon which was Y-derived, suggesting that the 3' portion of the Kallmann syndrome gene is essential for its function and cannot be substituted by the Y-derived homologous region53. These data indicate that abnormal pairing and homologous recombination occur between Xp22.3 and Yql 1.2, as previously hypothesized35. It could be predicted that this distinctive mechanism plays an important role in the majority of X/Y translocations involving the X short arm, although other mechanisms, such as non homologous recombination, may also be involved. No information is available about the molecular mechanisms underlying X/autosomal translocation involving the distal short arm of the X chromosome. Bodrug et al. studied three X/autosomal translocations involving other regions of the X chromosome and found that these were the result of non homologous recombination with minor additions or deletions at the junction point54-55. The breakpoints of terminal deletions involving the X
Downloaded from http://hmg.oxfordjournals.org/ at Michigan State University on January 23, 2015
X/Y translocations. X/Y translocations involving the distal short arm of the X chromosome can be divided into two major groups: Xp/Yp and Xp/Yq translocations. Xp/Yp translocations involving the testis determining factor (TDF) are found in sex reversed individuals (XX males or more rarely XY females)25 - 2 8 . Usually the translocation is not visible by cytogenetic analysis and can only be detected using molecular probes. Xp/Yq translocations29"41 (for references prior to 1985 see review by Bernstein R. and references therein29) have been easily recognized cytogenetically because of the presence of the highly fluorescent Y heterochromatic region (Yql 1-qter) located at the top of the distal Xp region. Both types of translocation events cause a terminal Xp deletion. Therefore, as in 'pure' terminal deletions, the length of the deleted region and the complexity of the phenotype depend on both the position of the breakpoint on the X chromosome and on the sex of the affected individual.
Human Molecular Genetics, Vol. 1, No. 4 223 chromosome have not yet been characterized. Recent studies of a patient with a terminal deletion of chromosome 16 associated with alpha thalassemia demonstrated that the loss of the telomere was stabilized by the addition of telomeric repeats (TTAGGG) at a specific recognition site for human telomerase56'57. It will be interesting to determine if this, or other mechanisms, are involved in Xp terminal deletions.
Clinical features I SS I CDPX | MRX | XLI | KAL |
Interstitial deletions
Terminal deletions, X/Y translocations -20 -10
Figure 1. ClinkaJ features of male patients with Xp22 deletions and translocations. SS = short stature, CDPX = X-linked recessive chondrodysplasia punctata, MRX = mental retardation, XLI = X-linked ichthyosis, KAL = X-linked Kallmann syndrome. Bold lines indicate presence of a disease phenotype. Numbers besides the bold lines indicate the approximate number of unrelated patients observed in whom the chromosomal rearrangement was demonstrated either by cytogenetic or molecular analysis.
Downloaded from http://hmg.oxfordjournals.org/ at Michigan State University on January 23, 2015
Clinical findings Male patients with deletions in Xp22.3 are nullisomic for this region and consequently they show contiguous gene syndromes characterized by different combinations of phenotypes according to the length of the deletion14 (see figure 1). These contiguous gene syndromes are characterized by the association of up to five of the following diseases (see ref. 1): short stature (SS;MIM312865), X-linked recessive chondrodysplasia punctata (CDPX; MIM3O295O), mental retardation (MRX; MIM309530), X-linked ichthyosis (XLJ; MIM3O81OO) due to STS deficiency and Kallmann syndrome (KAL; MIM30870O). The phenotype can be predicted in each patient from the results of molecular analysis. Figure 1 shows the variety of phenotypes which have been observed. In addition to these phenotypes, Schnur et al. reported a family in which several male members were affected by X-linked ichthyosis associated with ocular albinism type 1 (OA1; MIM3OO5OO) in which they demonstrated a deletion of the STS gene58. They hypothesized the presence of a contiguous gene syndrome involving both the STS and the OA1 genes. However, this hypothesis is not compatible with the absence of OA1 in patients with contiguous gene syndromes involving the STS and KAL genes, suggesting that the patients reported by Schnur et al. might have a complex rearrangement. Two independent linkage studies on families with OA1 have recently been published59*. They both support the assignment of OA1 to the Xp22.3 region, although they contain conflicting data about the relative order of OA1 with respect to the other loci in the region.
Female patients with terminal Xp deletions, X/Y translocations or X/autosomal translocations typically do not show any of the recessive diseases described in affected males because of the presence of a normal X chromosome. However, they almost invariably show short stature. This observation is consistent with the presence of a gene affecting height in the pseudoautosomal region, two active copies of which are needed for normal growth (MIM312865) 14-37. Recently, there have been several reports of female patients with terminal deletions and translocations involving the Xp22 region. These patients and their clinical features are listed in Table 2. Several of these patients share clinical features which are found in two Mendelian disorders, Aicardi syndrome (AIC; MIM3O4O5O) and Goltz syndrome (Focal Dermal Hypoplasia) (FDH; MIM305600). Aicardi syndrome, first reported by Aicardi et al.61, is defined by the occurrence of all of the following features: infantile spasms, agenesis of the corpus callosum and specific chorioretinal abnormalities called 'lacunae'. A recent study of 18 cases with Aicardi syndrome summarizes the spectrum of clinical manifestations of this disease62. Ophthalmologic findings may include punched-out chorioretinal 'lacunae' (areas of depigmentation of the retinal epithelium), microphthalmia, optic nerve coloboma, nystagmus and detached retina. Costovertebral defects have been observed in several cases. Although the pathogenesis of Aicardi syndrome is unknown, neuropathological findings suggest the presence of a neuronal migration defect involving several areas of the brain63. Goltz syndrome, also known as focal dermal hypoplasia, is characterized by typical cutaneous abnormalities almost invariably present from birth (see ref. 64 and 65 for review). These are areas of aplastic skin with a linear and asymmetric distribution, they can be hypo- or hyperpigmented, and can be found in any part of the body. Common findings in Goltz syndrome include microphthalmia, chorioretinal colobomata, sparse and brittle hair, nail dystrophy, oral and dental anomalies, and various types of skeletal abnormalities, as well as a wide spectrum of digital malformations. The pathogenesis of Goltz syndrome is also unknown. The multisystemic and congenital nature of the disease and the histological findings upon analysis of the skin lesions suggest the presence of a multiple field defect resulting from a complex developmental abnormality of the connective tissue65. Some of the patients listed in Table 2 have been diagnosed as Goltz syndrome and some as Aicardi syndrome. In two patients, the presence of a contiguous gene syndrome, involving both disease genes, was hypothesized24. In other cases, the phenotype showed some similarities with either Aicardi or Goltz syndromes, although the authors stated that the criteria to make such diagnoses were not met. We think that the clinical diagnosis of these syndromes generally follows very strict criteria that do not take into account clinical variability66-67. The definition of the clinical presentation of these syndromes is therefore biased because patients with 'incomplete' phenotypes are excluded. If patients identified with a different approach (i.e. cytogenetic) are included, then the spectrum of manifestations of a particular syndrome may broaden, consequently affecting the diagnostic criteria. An alternative explanation for the differences between the patients listed in Table 2 and the patients with 'classical' Aicardi and Goltz syndromes is the presence of genetic heterogeneity for these two diseases. However, in this case one would have to postulate two forms of these diseases, both with an X-linked 'dominant' inheritance pattern.
224 Human Molecular Genetics, Vol. 1, No. 4 Table 2. Clinical features of some female* patients with Xp22 deletions and translocations AICARDI SYNDROME
GOLTZ SYNDROME z
REFERENCE
Tenninal deletion (Xp22.31-pter)
2. Temple etal. 20
Terminal deletion (Xp22.2-pter)
3. AUansonelaJ.21 (case 1)
TenranaJ deletion (Xp22.2-pter)
4.Thie»«aL23
Tenrunal deletion (Xp22.3-pter)
5. Nantomj et al. 24 (caiel)
Terminal deletion (Xp22.3-pter)
6. Naritomietal. 24 (case 2)
Terminal deletion (Xp22.3-pter)
7. Magenii E (p.c.)
Terminal deletion (Xp22.2-pter)
Z
32
X/Y translocation (Xp22/Yq 11)
9. Al GazaJi el al.36 (caje 1)
X/Y translocation (Xp22.3/Yql 1.2)
3
10. Al Gazali el al * (ca>c 2)
X/Y translocalion (Xp22.3/Yq 11.2)
11. Hulten M. (p.c.)
X/Y translocalion (Xp22/Yp)
12. Ropers et al. 42
Balanced translocation"* (Xp22.2/3ql2)
13. Piombo et al. 43
Unbalanced translocation (Xp22. l/4
