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Human Molecular Genetics Pages 1657-1666

Progress in the autosomal segmental aneusomy syndromes (SASs): single or multi-locus disorders?
Introduction
Single Gene Disorders
   Alagille syndrome (syndromic bile duct paucity, arteriohepatic dysplasia)
   Angelman syndrome (AS)
Multi-Gene Disorders
   Williams syndrome (WS)
   Langer-Giedion syndrome (tricho-rhino-phalangeal syndrome type II)
Disorders Of Unknown Status (One Or Multiple Genes?)
   Prader-Willi syndrome (PWS)
   Miller-Dieker syndrome (MDS)
   Smith-Magenis syndrome (SMS)
   The 22q11 deletion disorders: DiGeorge and velocardiofacial syndromes (DGS/VCFS)
Summary
Acknowledgements
References

Progress in the autosomal segmental aneusomy syndromes (SASs): single or multi-locus disorders?

Progress in the autosomal segmental aneusomy syndromes (SASs): single or multi-locus disorders? Marcia L. Budarf and Beverly S. Emanuel

Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

Received June 12, 1997

Based on cytogenetic observations, several syndromes have been previously identified as microdeletion-based disorders. In this review, recent progress is presented regarding whether one or multiple genes can be implicated in the pathogenesis of these segmentally aneusomic syndromes. The syndromes discussed include Angelman, Alagille, Williams, Langer-Giedeon, Prader-Willi, Smith-Magenis, Miller-Dieker, and DiGeorge/velocardiofacial or the 22q11 deletion syndromes. For Angelman and Alagille syndromes, single genes have been identified, whereas for Williams and Langer-Giedion syndromes, more than one gene can be implicated. Although there has been significant progress in dissecting the molecular basis for the other disorders, the ultimate answer regarding one versus several genes remains to be determined.

INTRODUCTION

In 1986, Schmickel (1 ) applied the term `contiguous gene syndrome' to disorders resulting from the deletion or duplication of adjacent genes in a specific chromosomal region. One of the major criteria for classifying a disorder as a contiguous gene syndrome was that it had been identified as a recognizable clinical entity prior to its cytogenetic localization. By definition, this category of disorders excluded deletion- or duplication-based syndromes whose genomic location was known at the outset based on a recurrent cytogenetic abnormality associated with a specific and complex set of clinical features (e.g., cri-du-chat or Wolf-Hirschhorn). It was further suggested that for any given contiguous gene syndrome: (i) there would be some cases with and some without cytogenetic evidence of deletion or duplication; (ii) they would most often be sporadic; (iii) the extent of the chromosomal region involved in each case would correlate with the phenotype; and (iv) individual features of the syndrome might be inherited in isolation.

In the 11 years that have ensued since Schmickel's initial description, there have been numerous discussions regarding the appropriate terminology to use in categorizing these disorders. The original term `contiguous gene syndrome' is somewhat inaccurate because the genes responsible for the clinical features might not be truly contiguous. Thus, while numerous genes might be included within the deleted or duplicated genomic segment by virtue of their location, not all would be expected to have an effect on the resulting phenotype. Suggested alternatives, such as microdeletion syndrome (2 ), or contiguous deletion syndrome (3 ), do not adequately cover those syndromes resulting from duplications or imprinting abnormalities. In this review the term `segmental aneusomy syndromes (SAS)' is utilized to describe these disorders. This name, introduced at an American Society of Human Genetics meeting in 1990 [Am. J. Hum. Genet. (1990) 47, 22], is intended to imply that the pathogenesis of the disorder in question is the result of inappropriate dosage for critical genes within a genomic segment. This designation applies when the mechanism causing dosage imbalance is structural (by deletion or duplication), as well as when the dosage imbalance is functional (by imprinting defects or uniparental disomy).

In this review, we discuss recently published results on the molecular analysis of several autosomal disorders that are thought to result from segmental aneusomy. The SASs chosen for discussion are those deletions for which new information regarding their molecular dissection has emerged within the past 18 months. For this reason, the WAGR and Rubinstein-Taybi syndromes have not been included. WAGR is a well studied multi-gene disorder in which PAX6 (MIM 106210 Aniridia, Type II; AN2) and WT1 (MIM 194070 Wilms Tumor; WT1) are extensively characterized genes responsible for the pathogenesis of its major features. In contrast, the Rubinstein-Taybi syndrome appears to be due to mutations in a single gene, the CREB binding protein (CBP) (4 ). With regard to recent progress in other potential SASs, two disorders can no longer be placed in this category. Single genes have been identified which account for the complex phenotypes observed in both Alagille and Angelman syndromes. On the other hand, evidence has accumulated to suggest that more than one gene is responsible for the constellation of findings in patients with Williams and Langer-Giedion (Tricho-Rhino-Phalangeal Type II) syndromes. Further, although much progress has been made in the molecular dissection of the regions implicated in Prader-Willi, Smith-Magenis, Miller-Dieker and DiGeorge/velocardiofacial syndromes, definitive evidence regarding the involvement of one or multiple genes in these disorders has not yet emerged.

SINGLE GENE DISORDERS

Alagille syndrome (syndromic bile duct paucity, arteriohepatic dysplasia)

Alagille syndrome is an autosomal dominant disorder characterized by a paucity of intrahepatic bile ducts in association with cardiac, ocular and skeletal defects, and a typical facial appearance (5 ,6 ). Additional anomalies may include growth retardation, long bone abnormalities and renal disease. When probands are ascertained on the basis of hepatic disease in the neonatal period, the estimated frequency of this disorder is 1/100 000 live births. The clinical manifestations are quite variable. Some individuals with Alagille syndrome may present with jaundice and cholestasis during the first three months of life, while others, often parents and siblings of affected individuals, have few or no symptoms and often remain undiagnosed as adults (reviewed in 7 ).

The disease has been mapped to the short arm of chromosome 20 based on the identification of multiple patients with cytogenetically visible deletions and a family with an apparently balanced t(2;20)(q21.3;p12) translocation segregating with Alagille syndrome (reviewed in 7 ). The numerous Alagille syndrome patients with 20p deletions led to the initial hypothesis that Alagille syndrome might be a disorder caused by segmental aneusomy. However, the frequency of cytogenetically visible or submicroscopic deletions is lower in Alagille syndrome than in the other well studied SASs (<7%) (7 ). The 20p12 critical region spans 1.2-1.3 Mb and a YAC/P1/BAC contig covering this segment has been constructed (8 ,9 ). The human Jagged1 gene (JAG1), an excellent candidate for Alagille syndrome, has been positioned within the critical region by PCR amplification of a BAC in this contig (10 ) (Fig. 1 ).


Figure 1. Ideograms of the chromosomes involved in Alagille (20p) and Angelman (15q) syndromes. Both are now single gene disorders. The relevant genes are enclosed within the brackets which indicate their chromosomal localization.

The protein product of the human JAG1 gene is a ligand for the Notch transmembrane receptor (11 ). The Notch pathway has been shown to play a significant role in mediating cell fate decisions during embryonic development in vertebrates and invertebrates. The gene is expressed in human fetal liver, heart and kidney as well as in adult heart and kidney. Therefore, based on its function and 20p12 position, the JAG1 gene was tested as a candidate for Alagille syndrome. In four families, unique coding mutations have been identified in multiple affected individuals (10 ). Each of these mutations introduces a frameshift in a conserved region of the gene that would result in a gross alteration of the JAG1 protein product. The phenotype of affected individuals in each family is quite variable and some of the individuals with mutations are only mildly affected whereas others manifest all of the major features of Alagille syndrome. In six additional Alagille syndrome patients, mutations in JAG1 have also been identified (12 ). These data implicate JAG1 as the Alagille syndrome gene. Further, since deletions appear sufficient to cause the disease, haploinsufficiency for the JAG1 protein is a likely etiologic mechanism (10 ).

Angelman syndrome (AS)

Two clinically distinct disorders are associated with interstitial deletions of 15q11-q13, Angelman (AS) and Prader-Willi syndromes (PWS). Although the regions deleted in the majority of patients with these disorders overlap, AS results when the deletion occurs on the maternally inherited chromosome, while PWS results from deletions on the paternally derived chromosome (13 ). Individuals with AS are characterized by moderate to severe motor and mental retardation, a puppet-like ataxic gait, hypotonia, epilepsy, absence of speech, abnormal EEG, seizures, microcephaly, excessive and inappropriate laughter and unusual facies. The facial features often include a large mandible and an open mouthed expression with protruding tongue (reviewed in 14 ). The frequency of AS is presently unknown.

There are four groups of AS patients based on their cytogenetic or molecular status. Approximately 70% of individuals with AS demonstrate a visible or submicroscopic maternal deletion of 15q11-q13 (3-4 Mb). An additional 1-4% of patients exhibit paternal uniparental disomy (UPD). In ~7% of patients, defects in a putative imprinting center (IC) have been observed based on biparental inheritance of imprinted genes in the 15q11-q13 region with a paternal-only methylation pattern. The fourth category, which includes multi-generational pedigrees, demonstrates both biparental inheritance and appropriate methylation pattern of genes from the PWS/AS region (15 ,16 ). This rare mode of familial segregation has led to the suggestion that these latter cases could be the result of intragenic mutations in an AS gene, presumably a gene expressed only from the maternal homologue in some tissues.

The AS critical region lies telomeric to the PWS candidate region in proximal 15q. It was narrowed to 250 kb based upon molecular characterization of several rare translocation and deletion AS patients, as well as a patient with a 15q11.2q24.3 paracentric inversion (17 -19 ). Mapping data have demonstrated that the locus for E6-AP ubiquitin protein ligase (UBE3A) lies within this narrowed AS critical region (18 ) (Fig. 1 ). This gene product is involved in the ubiquitin mediated protein degradation pathway. Although there is biparental expression of UBE3A in fibroblasts and lymphoblasts, its position in the narrowed critical region and failure to identify maternally expressed transcripts in its vicinity led to re-examination of UBE3A as an AS candidate gene. Mutational analysis of UBE3A in AS patients without a known molecular defect (i.e., non-deletion/non-UPD/non-IC mutation patients) was performed. Multiple mutations in UBE3A, including two de novo frameshifts, one nonsense, two missense mutations and introduction of a novel splice junction, have been identified (20 ,21 ). Further, an additional study indicates that the 15q11.2 breakpoint of the previously mentioned AS paracentric inversion (see above) disrupts the UBE3A locus (19 ). Based on these findings, it has been proposed, but not yet demonstrated, that the UBE3A locus must produce a functionally distinct, maternally expressed gene product.

Progress has been made in characterization of AS patients who appear to have IC mutations. Recent studies have shown that microdeletions (as small as 6 kb) around and upstream of SNRPN exon 1 are sufficient to cause AS with imprinting mutations (22 ). The IC has been mapped to a 100 kb region between D15S63 and SNRPN exon 1, a region which includes several alternative 5' SNRPN exons referred to as BD1-3 (23 ). The transcripts produced from this region have various combinations of the BD and SNRPN exons and appear to have low protein coding potential. Further, these unusual transcripts are expressed exclusively from the paternal chromosome. Mutations within the BD exons have been described in seven AS families with IC mutations (23 ). It has been suggested that the IC acts, in cis, to reset the male -> female genomic imprint during oogenesis and the female -> male imprint during spermatogenesis. Thus, AS patients with IC mutations carry an ancestral paternal 15q11 -> q13 imprint pattern (epigenotype) on the mutant chromosome 15 (22 ).

MULTI-GENE DISORDERS

Williams syndrome (WS)

Williams syndrome (WS) (24 ,25 ) is a developmental disorder that includes cardiovascular anomalies, dysmorphic facial features, developmental delay with a unique cognitive profile, infantile hypercalcemia and growth retardation. The frequency of WS is estimated to be ~1/10 000 (26 ). Most cases are sporadic and the molecular basis of the disorder was unknown until 1993. At that time Ewart et al. (27 ) demonstrated linkage of isolated familial supravalvular aortic stenosis (SVAS) to the elastin gene (ELN). Since SVAS is also a component of WS, they examined WS patients for mutations in ELN. In contrast to isolated familial SVAS, the WS patients were found to have large deletions encompassing the entire ELN gene, suggesting that WS may be due to a microdeletion of chromosomal region 7q11.23 (28 ). Subsequent work has confirmed this observation (Fig. 2 ). A number of studies have shown that deletions occur with approximately equal frequency on the maternally or paternally derived chromosome, suggesting that imprinting is not involved in the major features of the phenotype. However, significantly more severe growth retardation and microcephaly has been noted in children with deletions arising on the maternal chromosome (29 ).


Figure 2. Ideograms of the chromosome involved in Williams (7q) and Langer-Giedion (8q) syndromes. Both are disorders in which more than a single gene has been implicated. The known genes are enclosed within the brackets which indicate their chromosomal localization. Additional genes have been identified in the WS critical region (see text), but their role in the WS phenotype has not yet been determined. Question marks indicate that additional genes have been postulated to account for features of the phenotype not currently explained by defects in the known genes.

Physical and genetic maps of the WS region of chromosome 7 and molecular analysis of patients suggests that the region consistently deleted is ~2 cM or 2 Mb (29 -32 ). Further, there is evidence that the deletions are due to unequal interchromosomal rearrangements (31 ,33 ), perhaps related to the presence of duplicated sequences at the deletion breakpoints (29 ,30 ). cDNA selection, using cosmids representing 400 kb of the WS critical region, identified four novel transcripts (WSCR1-4) and an EST. While two of the transcripts, WSCR2 and -3, have no matches in GenBank, WSCR1 has homology to RNA binding proteins and WSCR4 shows homology to an intermediate filament-associated protein, restin (32 ). Two additional genes have been mapped to the deletion interval, replication factor C subunit 2 (RFC2) (34 ) and LIM-kinase1 (LIMK1) (35 ). LIMK1 is a novel kinase with two zinc-binding motifs (LIM domains) and is strongly expressed in the brain. Further, two families with `partial WS' (affected family members display the WS cognitive profile and SVAS, but lack other features of WS) and smaller deletions that include only ELN and LIMK1 have been identified. This provides strong evidence that the cognitive abnormalities in WS are due to haploinsufficiency of LIMK1 (35 ). Thus, it is likely that the loss of at least three genes is required for the full WS phenotype.

Langer-Giedion syndrome (tricho-rhino-phalangeal syndrome type II)

Patients with Langer-Giedion syndrome/tricho-rhino-phalangeal syndrome type II (LGS/TRPS II) exhibit the clinical features of tricho-rhino-phalangeal syndrome type I (TRPS I), together with multiple cartilaginous exostoses and mental retardation. TRPS I is characterized by sparse scalp hair, large protruding ears, bushy eyebrows, a broad nasal bridge, bulbous nose, elongated upper lip with a thin upper vermilion border, and cone-shaped epiphyses. Malocclusion, mandibular retrognathia and dental abnormalities are also common. There is frequently marked laxity of the skin in infancy and early childhood, a feature which diminishes with age. Although patients with TRPS I have normal intelligence, mild to moderate mental retardation is often seen in LGS/TRPS II (36 ). A terminal deletion of chromosome 8q [del(8)(q24)] in a patient with features of LGS/TRPS II was reported in 1980 (37 ). Subsequently, deletions or other rearrangements involving 8q24 have been identified in the majority of patients with this disorder (Fig. 2 ). Recent studies demonstrate no parent of origin effects in LGS/TRPS II as both paternal and maternal deletions have been observed (38 ).

Since LGS/TRPS II is associated with multiple exostoses, it was hypothesized that a gene for hereditary multiple exostoses (EXT1) might also map to 8q24. Hereditary multiple exostoses is an autosomal dominant disorder characterized by bony protuberances (exostoses) at the growth plates of the long bones. A linkage study confirmed the presence of one locus for multiple exostoses in 8q24 with evidence for other loci on chromosomes 11 and 19 (39 ). EXT1, a cDNA that spans the 8q24 chromosomal breakpoints of two patients with multiple exostoses has been isolated (40 ). This cDNA has no obvious homology to known genes and has been shown to harbor frameshift mutations segregating with affected individuals in EXT1 families (40 ). It is also deleted in all LGS/TRPS II patients (40 ). The genomic organization and promoter structure of the EXT1 gene has been determined (41 ). The gene has 11 exons, spans 350 kb of genomic DNA and has a large CpG island which contains GC and CAAT boxes but no TATA box (41 ).

The results presented above suggest that at least two genes appear to be responsible for LGS/TRPS II; EXT1 and TRPS, the gene hypothesized to be deleted/mutated in TRPS I and II patients. Thus, LGS/TRPS II is a multiple gene deletion syndrome, and is not due to the pleiotropic effects of mutations in a single gene. A separate gene for mental retardation has been suggested based on several LGS/TRPS II patients with smaller deletions and normal intelligence (42 ). The area likely to contain such a locus has been narrowed by the recent description of two patients with normal intelligence, TRPS I, and deletions that partially overlap the LGS/TRPS II critical region (38 ,43 ). This supports the hypothesis that a gene for mental retardation lies outside the TRPS I region.

DISORDERS OF UNKNOWN STATUS (ONE OR MULTIPLE GENES?)

Prader-Willi syndrome (PWS)

Prader-Willi syndrome (PWS) is a neurobehavioral disorder characterized by severe hypotonia, poor suck and hypogonadism in the neonatal period. It occurs at a frequency of ~1/15 000 (22 ). Individuals with PWS exhibit failure to thrive in infancy which is succeeded by hyperphagia leading to obesity. Patients have mild to moderate mental retardation, behavioral disorders and a characteristic facial appearance which includes almond shaped eyes, narrow bitemporal diameter, upslanting palpebral fissures and strabismus. Additional features include short stature and small hands and feet. The majority of patients (>70%) have a cytogenetically visible deletion of 15q11-q13 on the paternally derived chromosome while an additional 25% of patients demonstrate maternal UPD (14 ) (Fig. 3 ). A few patients are presumed to carry mutations in an IC (44 ).


Figure 3. Ideograms of the chromosome involved in Prader-Willi (15q), Miller-Dieker (17p), Smith-Magenis (17p) and DiGeorge/velocardiofacial syndromes (22q). All are disorders for which the question regarding involvement of one or multiple genes has not been definitively answered. The known genes and transcripts are enclosed within the brackets which indicate their chromosomal localization. For Miller-Dieker syndrome, the question marks indicate that additional genes have been postulated to account for features of the phenotype not currently explained by defects in the LIS1 gene.

The PWS critical region encodes several imprinted, paternally expressed genes and transcripts. The genes include ZNF127 (22 ) and SNRPN (45 -47 ), the gene for the small ribonucleoparticle (snRNP)-associated protein N. The region also contains several transcripts that appear to have no significant ORFs; PAR5 (48 ), IPW (49 ), PAR1 (48 ) and the recently described PAR-SN (50 ). Three new SNRPN exons with low protein coding potential have been identified at the 3' end of the gene (KB1-3) (51 ). One of these (KB3) partially overlaps with the PAR-SN transcript. It appears that SNRPN is part of a large and somewhat complex transcription unit which produces coding and non-coding transcripts. To determine the role of these genes and transcripts in the PWS phenotype, several new PWS-associated balanced translocations have been analyzed. One disrupts SNRPN, preventing the production of full-length SNRPN transcripts while leaving expression of ZNF127, PAR5, IPW and PAR1 intact (52 ). The second translocation breakpoint, lies between PAR5 and IPW and shows normal SNRPN and PAR5 expression but loss of expression of the more distal transcripts, IPW and PAR1. Although the first translocation implicates loss of SNRPN expression as causative for PWS, the second rearrangement suggests that PWS can occur in the presence of SNRPN expression. Additional studies will be required to resolve this apparent discrepancy.

In 3/3 PWS IC mutation families, there is a deletion of the first exon of SNRPN (23 ). However, since one of these three patients has a microdeletion which does not overlap the smallest of the AS IC deletions, it has been suggested that the IC has a bipartite structure (22 ,23 ). The model suggested for this structure includes an imprintor, a downstream site that initiates the imprint switch and implicates the involvement of previously described alternative SNRPN transcripts (23 ). Thus, a defect in the imprintor fails to initiate a paternal -> maternal imprint switch causing AS while a defect in the initiation site blocks the maternal -> paternal switching resulting in PWS. This hypothesis takes into account the data from analysis of AS and PWS families with IC mutations. Testing the model is not currently feasible, as it would require analysis of the germline.

Miller-Dieker syndrome (MDS)

Miller-Dieker syndrome is characterized by lissencephaly (`smooth brain'), severe to profound mental retardation and a characteristic facial appearance consisting of a prominent forehead, bitemporal hollowing, short nose with upturned nares, protuberant upper lip and small jaw (53 ). Other abnormalities seen in MDS include heart defects, growth retardation and seizures (53 ). Over 90% of MDS patients have visible or submicroscopic deletions of 17p13.3 (54 ) (Fig. 3 ). Most cases are the result of de novo deletions, but multiple affected sibs have been reported in families with a parental chromosomal rearrangement (55 ). Isolated lissencephaly (ILS) has also been linked to 17p13.3 with one-third of ILS patients having deletions detectable by FISH analysis (56 ). In general, ILS patients have severe mental retardation and may have some mild facial dysmorphia similar to MDS, such as bitemporal hollowing and small jaw, but they rarely have other consistent anomalies. The region critical to MDS has been narrowed to 350 kb (57 ) and a gene, termed LIS1, has been mapped to the critical region (58 ). Apparent non-overlapping deletions of LIS1 in one MDS patient and one ILS patient suggested that LIS1 was etiologic for both disorders (58 ). LIS1 is the human homologue of the 45 K subunit of an isoform of platelet-activating factor (PAF) found in bovine brain cortex (59 ). PAF is believed to be a transmitter in the central nervous system (59 ).

Recent re-evaluation of the LIS1 gene has shown that one of the original cDNA clones (8-1), which was thought to contain the 5' end of the LIS1 gene, is a chimeric clone. Clone 8-1 contains sequences from the LIS1 gene and a gene, 14-3-3[epsilon], which surprisingly is located more distally on the same chromosomal sub-band (3 ) as LIS1 (60 ). The 14-3-3[epsilon] gene maps outside of the MDS/ILS critical region and does not appear to be involved (60 ). A 500 kb cosmid/PAC contig has been constructed and the genomic structure of LIS1 gene has been characterized, including the correct 5' region of the gene (61 ). ILS and MDS patients have been analyzed for point mutations and deletions in LIS1 (61 ,62 ). Point mutations in the LIS1 gene have been found in three ILS patients, as well as an intragenic deletion and a reciprocal translocation in two additional ILS patients, providing strong evidence that the LIS1 gene is responsible for the lissencephaly seen in ILS and MDS (61 ,62 ). All but two of the MDS patients studied are deleted for the entire LIS1 gene. These two MDS patients have deletions with proximal end points within LIS1 (61 ). However, deletions in MDS patients always extend more distally than those in the deleted ILS patients, suggesting that additional genes located telomeric to LIS1 might be involved in MDS (61 ).

Smith-Magenis syndrome (SMS)

Smith-Magenis syndrome (SMS) was first described in 1982 (63 ). Since that time close to 100 patients have been reported (64 ) and the frequency is estimated to be 1/25 000 live births (65 ). The phenotype includes brachycephaly, ear malformations, midfacial hypoplasia, brachydactyly, mental retardation, self-destructive behavior and REM sleep abnormalities (65 -68 ). Using high resolution cytogenetics, the vast majority of patients have visible deletions of 17p11.2 (Fig. 3 ). A recent study of 62 SMS patients demonstrated that most share a common deletion interval with the proximal breakpoint between D17S58 and D17S446, and the distal breakpoint between cCI17-638 and cCI17-498. A small number of patients had breakpoints within the common deletion interval, allowing for narrowing of the critical region. All 62 patients were tested with the marker D17S258 and found to be deleted (64 ). A YAC/PAC/cosmid map covering >6 Mb, which encompasses the SMS critical region, has recently been published (69 ). The SMS critical region was found to be underrepresented in YACs and 16 new STSs were developed as part of the effort to isolate PACs and cosmids to span this region. Four genes, the small nuclear RNA U3 (RNU3) gene (70 ), the human homologue of the Drosophila flightless-I gene (FLI) (71 ), the gene encoding a human microfibril-associated protein (MFAP4) (72 ) and the gene encoding cytosolic hydroxymethyltransferase (SHMT1) (73 ), as well as four ESTs, were precisely ordered within the critical region (69 ). Lastly, a brain finger protein gene, ZNF179, has been shown to be deleted in 6/6 SMS patients tested (74 ). The position of ZNF179 relative to the genes/ESTs in the map by Wilgenbus et al. is not known. Additional studies are required to determine the role of these genes and transcripts in SMS.

The 22q11 deletion disorders: DiGeorge and velocardiofacial syndromes (DGS/VCFS)

A number of genetic disorders have been associated with deletions of chromosomal region 22q11 (Fig. 3 ). These include DiGeorge syndrome (DGS), velocardiofacial syndrome (VCFS), conotruncal anomaly face syndrome (CTAF), isolated and familial forms of conotruncal cardiac defects (reviewed in 75 ). DGS is characterized by conotruncal cardiac anomalies, aplasia or hypoplasia of the thymus and parathyroid glands, and mild craniofacial dysmorphia (76 ,77 ). The major features of VCFS are palatal and cardiac defects, learning disabilities and facial dysmorphia (78 ). CTAF shares features in common with VCFS and is presumed to be the same disease ascertained in a different ethnic group (79 ). The 22q11 deletion is estimated to occur at a high frequency in the general population (1/3000-4000 live births) (80 ). Using molecular techniques, microdeletions of the same region of 22q11.2 have been found in >90% of patients with DGS and >85% of VCFS/CTAF patients (81 ,82 ). Since the disorders associated with the 22q11 deletion appear to share a common etiology, they have been referred to collectively as the 22q11 deletion syndrome (75 ).

The major anatomical structures involved in the 22q11 deletion syndrome are derived from the cephalic neural crest cells leading to the proposal that abnormalities in early migration or colonization of neural crest cells may be responsible for the observed defects (83 ). Numerous genes have been identified within the region of 22q11.2 most commonly deleted (Table 1 ). Although several of these genes have been suggested as potential candidates for the disorder, it has not been possible to unequivocally identify any single gene responsible for the observed phenotype or for any of the individual features.

Table 1 Genes within the DGCR (centromere to telomere)
Gene Reference
DGCR6 100
LAN/DGCR2/IDD 101-103
TSK2 (serine/threonine kinase) 88, 104
DGS-I/ES2 88, 105, 106
GSCL (goosecoid-like) 89
CTP (citrate transport protein) 107, 108
CLTCL (clathrin heavy chain-like) 88, 91, 109, 110
HIRA 111, 112
hCDCrel-1 113
GP1BB 114
TBX-1 115
COMT 116
ARVCF 117
T10 118
N41 cDNA 119
LZTR-1 120
ZNF74 121

The region consistently deleted in the majority of patients is large (>1.5 Mb) and efforts have been directed towards determining the minimal DGS/VCFS critical region (MDGCR). Using breakpoint mapping data from a series of balanced or unbalanced translocations in patients with features of DGS/VCFS, different MDGCRs have been reported. Until recently, the proximal boundary was positioned between D22S427 and the only known DGS-associated balanced translocation, ADU, a t(2;22)(q14.1;q11.1) (84 ). However, a report of a patient (patient `G') with an interstitial deletion whose proximal boundary is distal to the ADU breakpoint, suggests that the proximal boundary of the MDGCR could be narrowed further (85 ). The distal boundaries differ, based on the locations of independent translocation breakpoints (86 -88 ).

The smallest region of deletion (SRD) is <160 kb with the distal boundary at the breakpoint of a t(15;22)(p11;q11) translocation (89 ,90 ). Only three genes reside within this interval: Goosecoid-like (GSCL), citrate transport protein (CTP) and clathrin heavy chain-like (CLTCL) (89 ). CTP is an integral membrane protein whose function is to move citrate across the mitochondrial inner membrane. CLTCL has significant homology to clathrin heavy chain, which is a major structural component of coated pits and coated vesicles. Although clathrin heavy chain is ubiquitously expressed, CLTCL is expressed predominantly in adult skeletal muscle. Recently a patient with a balanced translocation that disrupts the CLTCL has been identified (91 ). This patient has some, but not all, of the features seen in the 22q11 deletion syndrome suggesting that loss of more than one gene may be required for DGS/VCFS. GSCL is a homeobox gene of the paired-like class and has highest similarity to goosecoid, a gene that is expressed in neural crest-derived tissues. Further, GSCL is expressed early in fetal development, notably in the brain (Gottlieb et al., unpublished). The potential role of GSCL as a developmental control gene, make it an outstanding candidate for some of the abnormalities seen in the 22q11 deletion syndrome. However, studies of other disease-related genes have demonstrated that chromosomal rearrangements at a considerable distance from the causative gene can affect expression (e.g., 92 -94 ). Thus, genes upstream and downstream of the SRD remain potential candidates for the 22q11 deletion syndrome phenotype. These genes would include DGCR6, LAN/IDD/DGCR2, TSK2, DGSI/ES2, HIRA, UFD1L, hCDCrel-1 and TBX1 (Table 1 ).

Studies to examine the developmental expression of several of these candidate genes have been initiated in mouse and chick embryos (95 -98 ). With the exception of CLTCL, characterization of the MDGCR homologous region on mouse chromosome 16 has revealed extensive similarities in gene content, gene order, exon composition and transcriptional direction (99 ). These findings set the stage for further dissection of the phenotype in mouse embryos rendered haploinsufficient for the MDGCR. In all likelihood, such studies will prove to be essential because, despite significant efforts, neither intragenic deletions nor point mutations in candidate genes have been detected using patient samples.

SUMMARY

In summary, it is clear that significant progress has been made in dissecting the segmentally aneusomic syndromes. In retrospect, it is interesting to return to Schmickel's 1986 paper (1 ) in which the concept of `contiguous gene syndromes' was introduced. In it he stated that `clinical genetics combined with cytogenetics and molecular genetics can provide the essentials for the discovery of the causes of developmental defects. It is important to use clinical information to locate developmental genes.' How remarkably prophetic these concepts were, as we look at the developmental genes which have been discovered in this context during the past 11 years.

ACKNOWLEDGEMENTS

This paper is dedicated to the memory of Roy D. Schmickel whose conceptualization of `contiguous gene syndrome' (segmental aneusomy) continues to be an inspiration. These studies were supported in part by grants HL51533 and DC02027 from the National Institutes of Health.

REFERENCES

1 Schmickel,R.D. (1986) Contiguous gene syndromes: A component of recognizable syndromes. J. Pediatr. 109, 231-241. MEDLINE Abstract

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115 Chieffo,C., Garvey,N., Roe,B., Zhang,G., Silver,L., Emanuel,B.S. and Budarf,M.L. (1997) Isolation and characterization of a gene from the DiGeorge chromosomal region (DGCR) homologous to the mouse Tbx1 gene. Genomics, in press.

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117 Sirotkin,H., ODonnell,H., Dasgupta,R., Halford,S., Stjore,B., Pubch,A., Parimoo,S., Morrow,B., Skoultchi,A., Weissman,S.M., Scambler,P. and Kucherlapati,R. (1997) Identification of a new human catenin gene family member (ARVCF) from the region deleted in velo-cardio-facial syndrome. Genomics 41, 75-83.

118 Halford,S., Wilson,D.I., Daw,S.C.M., Roberts,C., Wadey,R., Kamath,S., Wickremasinghe,A., Burn,J., Goodship,J., Mattel,M-G., Moormon,A.F.M. and Scambler, P.J. (1993a) Isolation of a gene expressed during early embryogenesis from the region of 22q11 commonly deleted in DiGeorge syndrome. Hum. Mol. Genet. 2, 1577-1582. MEDLINE Abstract

119 Emanuel,B.S., Driscoll,D., Goldmuntz,E., Baldwin,S., Biegel,J., Zackai,E.H., McDonald-McGinn,D., Sellinger,B., Gorman,N., Williams,S. and Budarf,M.L. (1993) Molecular and phenotypic analysis of the chromosome 22 microdeletion syndromes. In Epstein,C.J. (ed.) Phenotypic Mapping of Down Syndrome and Other Aneuploid Conditions, Wiley Liss, New York, NY. pp.207-224.

120 Kurahashi,H., Akagi,K., Inazawa,J., Ohta,T., Niikawa,N., Kayatani,F., Sano,T., Okada,s. and Nishisho,I. (1995) Isolation and characterization of a novel gene deleted in DiGeorge syndrome. Hum. Mol. Genet. 4, 541-549. MEDLINE Abstract

121 Aubry,M., Demczuk,S., Desmaze,C., Aikem,M., Aurias,A., Julien,J-P. and Rouleau,G.A. (1993) Isolation of a zinc finger gene consistently deleted in DiGeorge syndrome. Hum. Mol. Genet. 2, 1583-1587. MEDLINE Abstract

Correspondence can be addressed to either author. Tel: +1 215 590 3856; Fax: +1 215 590 3764; Emails: budarf@cbil.humgen.upenn.edu beverly@mail.med.upenn.edu

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