Deletions of human chromosome 22 and associated birth defects

Deletions of human chromosome and ‘associated birth defects

22

Peter J. Scambler Institute

of Child

Health,

London,

UK

Investigations into the genetic basis of DiCeorge syndrome have shown that in the majority of cases there are DNA deletions from the long arm of chromosome 22, at 22qll. Similar deletions are now known to be present in a wide range of conditions with overlapping clinical features, and are an important cause of familial congenital heart defect. Deletions within 22qll have also been identified in individuals with no clinical complications. Current

Opinion

in Genetics

and Development

Introduction Several of the more common chromosomaf aneuploidies are associated with dysmorphic syndromes. In these cases, abnormal gene dosage is presumed to disrupt normal embryogenesis. Recent descriptions of dysmorphologies associated with the abnormal dosage of genes within a defined subchromosomal region has helped researchers formulate the concept of segmental aneusomy and contiguous gene syndrome [ 11. Over the past three years there has been increasing interest in the analysis of deletions within the proximal region of the long arm (q) of chromosome 22. This review summarizes recent investigations of this region and attempts to dissect what appeared at Rrst sight to be another contiguous gene deletion disorder, the DiGeorge syndrome (DGS).

Clinical

and historical

introduction

DGS is characterized by the absence or hypoplasia of the thymus, absence or hypoplasia of the parathyroids, cardiac malformations and dysmorphic facial features. The syndrome usually occurs sporadically, but it may be inherited as an autosomal dominant condition. The incidence has been estimated at 1 in 20000, but this is an underestimate based on the ascertainment of severe cases. In 1981, De la Chapelle and colleagues [2] reported the cytogenetic analysis of a large family with four children affected with DGS. AU four patients had an unbalanced translocation involving chromosomes 20 and 22 that gave rise to trisomy for the short arm (p) of chromosome 20 and monosomy for proximal 22q and 22~. As trisomy 2Op does not share the main features of DGS it was postulated that monosomy 22pter-22qll was

1993, 3:432-437

responsible for the dysmorphology. The following year, three cases of monosomy 22pter-22qll were reported in patients with DGS, with different autosomes carrying 22qll-22qter in each case. Thus, the relationship between monosomy for proximal 22 and DGS was established. The region critical for the development of the haploinsufficiency - the DiGeorge critical region (DGCR) - was further refined by the exclusion of the short arm: DGS was found in patients with interstitial deletions of 22ql1, patients with ring chromosome 22 did not have DGS, and a patient with an apparently balanced 2;22 translocation was described. The DGS phenotype has been reported in association with chromosome abnom&ities other than monosomy 22qll; in particular with monsomy lop [ 31, with homozygous inactivation of the Howi7 (Hoxl.5) gene in mice [4], with retinoic-acid embryopathy, and with several other teratogenic effects including the foetal alcohol syndrome. With these data in mind several commentators preferred to use the term DiGeorge anomaly to reflect the presumed aetiologic heterogeneity of the condition.

Mapping region

the DiGeorge

syndrome

critical

The small size of chromosome 22 has hindered precise cytogenetic mapping of the DGCR, and over the past two years molecular genetic methods have been employed to further refine the localization of the region important for the development of haploinsuficiency. Accordingly, DNA probes from proximal 22q have been isolated from a number of sources, including flow sort libraries [S-7] and microdissection/microcloning libraries [ 81. Several features have emerged from these molecular studies.

Abbreviations COMT-catechol-O-methyl FISH-fluorescence

432

in situ SRO-shortest

transferase; DCCR-DiCeorge

critical region; DCS-DiCeorge syndrome; ES-embryonic stern; hybridization; PFCE-pulsed-field gel electrophoresis; RFLP-restriction fragment length polymorphism; region of overlap; VCFS-velo-cardio-facial syndrome; VSD-ventricular septal defect.

@ Current

Biology

Ltd ISSN 0959437X

Deletions

of human

Firstly, the deletion breakpoints do not appear to cluster, which allows a ‘shortest region of overlap’ (SRO) map to be constructed. Secondly, DGS is often associated with submicroscopic deletion within 22qll [9,10**]. A recent prospective cytogenetic study DGS found interstitial deletions in nine out of the 36 cases assessed [ 1 l]. No other form of chromosome rearrangement was seen. Those patients in which no deletion was detected using high-resolution cytogenetics were almost invariably shown to possess interstitial deletions when tested using quantitative Southern-blot analysis and/or fluorescence in situ hybridization (FISH) [ 121. There was no discernable correlation between the extent of deletion and severity of phenotype: patients with no detectable deletion, or a deletion detected by means of a single marker may be severely affected, whereas those with visible deletions 22pter-22qll may be only mildly affected [7,11,13]. This variability was observed within families comprising mildly affected adults and severely affected children. Using restriction fragment length polymorphism (RFLP) studies Driscoll et al. [lo**] were able to exclude imprinting as having a major influence on the phenotype of DGS patients. Although, as stated above, the deletion breakpoints do not appear to coincide at recombination ‘hot-spots’, it has been difficult to narrowly define the DGCR as the majority of patients have a large deletion. In a Philadelphiabased study, 10 appropriate DNA probes were used to study 19 cases. An SRO was established, but it Included three loci covering at least 750 kb, as determined by pulsed-field gel electrophoresis (PFGE) [l@*].

(a)

chromosome

22 and associated

birth

defects

Scambler

433

The utilization of cosmid probes for FISH analysis of DGS [14] has enabled the identification of several low copy repeat families dispersed over 22qll [ 15.1. Some repeats cross-hybridize with sequences present at acrocentric centromeres and are probably related to alphoid repeats. Intriguingly, one cosmid containing a low copy repeat hybridizes strongly to the heterochromatlc region of chromosome 16. Other repeats are restricted to 22qll and may have a copy number as low as two. Repeat units from the same family may be located within and outside the region commonly deleted in DGS. Several repeats have been studied in a cell line, ADU, from a DGS patient that contains a balanced 2;22 translocation. All the probes thus far examined harbour repeat units located on both sides of the chromosome 22 breakpoint. Using a single probe (laboratory name ~~11.1) that detects two loci within 22qll and a series of cosmids detecting single loci with FISH, a molecular cytogenetic map of the DGCR has been established (E Lindsay, et aA, unpublished data) (Fig. 1). The majority of patients (>90%) are hemizygous for both ~~11.1 repeat units, which are at least 1 Mb and probably 2 Mb apart. This corresponds to the large size of the region that was found to be commonly deleted in DGS using PFGE analysis. However, in two of the patients, only the proximal scll.1 repeat unit is hemizygous. This locus is proximal to the balanced translocation breakpoint in the ADU cell line; thus, localizing the translocation breakpoint to an SRO of at least 500 kb. Any causal relationship between the presence of low copy number repeats at 22qll and the occurrence of

(b)

22P mcCOS*

CEN

22q

DCCR BCR

1

SC1 1.1* (proximal) scF5 sc4.1 scll.l* (distal) mcCOS*

L

I

SRO (-500

kb)

Commonly deleted

Fig. 1. Mapping of the DiGeorge-syndrome critical region (DO to chromosome 22. (a) Ideogram of chromosome 22pter-22ql1, with the centromere KEN) and breakpoint cluster region U3CR) indicated. fb) Map of the DCCR. The commonly deleted region and shortest region of overlap (SRO) are indicated, as is the position of a balanced 2;22 translocation breakpoint. DNA probes are shown, with those used to identify the members of several low copy repeat families dispersed over 22qll indicated with asterisks.

.

434

Mammalian genetics

deletions within the region has yet to be established; however, similar repeats have been she- to occur at the deletion breakpoints associated with steroid sulphatase deficiency [ 161. The number of cases of DGS studied using molecular probes from my laboratory is now well over 100, and includes several unpublished cases communicated to me by different several laboratories located in the UK and Europe. Two DGS patients with no apparent chromosome 22 rearrangement have been identified. This conEnns that the pr&iously discussed phenocopies of DGS must occur rarely as clinical problems. The use of DNA analysis in a diagnosis setting, as an adjunct to clinical assessment, is now well established. The use of FISH as an antenatal diagnostic tool in ‘at risk pregnancies has also been muted [ 171 and, in one case in the UK, implemented. Counselling in these circumstances is difhcult because although any foetus carrying a deletion within 22qll is undoubtedly at risk of being born with cardiac or other malformations, there is as yet no good molecular test to support prognosis, and many of the anomalies are surgically correctable.

The velo-cardio-facial syndromes

and DiCeorge

There is a striking degree of phenotypic overlap between DGS and the Shprintzen or velo-cardio-facial syndrome (VCFS) [ 181; some published cases of DGS have been retrospectively rediagnosed as VCFS [19]. VCFS is a disorder with multiple malformations including cleft palate (it is the commonest cause of syndromal oro-facial clefting), cardiovascular anomalies and learning difficulties; over 30 manifestations have been described [20]. The patients have characteristic facial features, including a prominent nose, broad nasal root, narrow palpebral Iissures and retrognathia. Cardiac defects are found in 85% of patients, the most common abnormality being ventricular septal defect (VSD) with or without a right aortic arch. Almost all patients have some form of leaming or behavior diiliculty, with mild mental retardation and microcephaly present in many cases. Psychosis is a feature in some adolescent and adult patients. Using FISH and quantitative Southern-blot analysis we have found that the loci commonly deleted in DGS are also hemizygous in VCFS patients [21**,22]. Similar findings have been reported in an independent study [23**]. Both analyses demonstrate that the critical region for DGS is the same as that for VCFS at the resolution afforded by current markers; that is, the region commonly deleted in VCFS is large. Evidently, this means that a correlation between size or deletion position and clinical phenotype cannot be made. Presumably, VCFS is caused by a haploinsufficiency for the same gene or set of genes as DGS.

Congenital syndrome

heart

disease

and DiCeorge

The clinical variability seen in patients with hemizygosity at 22qll is emphasized by the analysis of one family ascertained through a proband with severe DGS (the symptoms included an interrupted aortic arch, VSD, necrotising enterocolitis, hypocalcaemic seizures, left-sided renal aplasia and bilateral talipes equinovarus) [24*]. The proband has three siblings, an unaffected sister, one brother with a VSD and another brother with a coarctation of the aorta and a patent ductus arteriosus. The brothers and mother also exhibit mild crania-facial dysmorphism; the mother’s heart is normal and the father is unaffected. The three children with cardiovascular defects and the mother have an interstitial deletion of 22q, which was detected using high-resolution cytogenetics. The deletion was confirmed by quantitative Southern analysis and FISH. This demonstrates once again that it is possible to have a relatively mild dysmorphology associated with hemizygosity for several megabases of 22qll; evidently, such hemizygosity is compatible with a normal lifestyle. At the same time, however, this hemizygosity predisposes to severe birth defects. A lysis of this family also highlights that isolated conger d heart defects can be associated with deletions within 22qll; were it not for the DGS child the chromosomes of other family members would not have been examined. The results of this study have prompted the investigation of familial, non-syndromic congenital heart defects. A set of nine families with familial congenital heart defects was recently ascertained in the UK [25**]. FISH and quanititative Southern-blot analysis were again employed to detect hemizygosity within 22qll. Five of the nine families were found to have a deletion that was detectable using the marker HP500/sc4.1. In one of these families, a deletion was present in the unaffected father of affected children. A remarkable iinding was that deletions were detected in families where the nature of the cardiac anomaly varied between individuals of a family, but not in cases where the heart defect was anatomically identical. The significance of this correlation has yet to be established, but in a subsequent family study, where two sisters had tetralogy of Fallot, no deletion was detected. A summary of the cardiac malformations found in this series of patients with 22qll deletions is given in Table 1. It is of course possible that in some of the cases with no detectable hemizygosity smaller deletions are present (especially as only one probe was used in the study>, or that point mutations within DGCR genes may give rise to cardiac defects. It is possible that other syndromes will be found with associated hemizygosity at 22qll. One case of Noonan syndrome in a child with DGS and interstitial deletion of 22qll has been described [26]. Noonan syndrome sometimes occurs in association with neurolibromatosis (NFl) and deletions of neuroiibromin; thus, it is evident that Noonan syndrome is genetically heterogeneous. Other disorders, such as Kousseff syndrome, share fea-

Deletions

Table

1. Cardiac

defects

with

Tetralogy Right aortic

abnormalities

hemizygosity

observed

for a region

in familial

of human

heart

of 22qll.

of Fallot

22 and associated

birth

defects Scambler

of more than one critical gene, and the possibility of anticipation is an area currently under investigation in my laboratory. However, the relevance of chance should not be ignored in this situation [ 271, and in my opinion could account for much of the variation seen clkrically.

arch

Pulmonary

atresia

Ventricular

septal

Anomalous

left or right

defect subclavian

artery

Dextrocardia Interrupted

chromosome

aortic

arch

tures with DGS/VCFS, but there has not yet been the opportunity to examine DNA from such patients. Familial congenital heart disease is rare; the risk of congenital heart disease in offspring of patients with corrected tetralogy of Fallot is approximately 3%. However, individuals hemizygous for sequences within 22qll may be free of heart disease, and parents with heart defects and a deletion may have children who although they have inherited a deletion, have no heart disease. Considering these phenomena, and the occurrence of new mutations (e.g. de nouo deletions), it is likely that a proportion of patients with sporadic congenital heart disease will have hemizygosity at 22qll. In the preliminary studies reported to date, Professor Emanuel’s group have detected deletions in 2/11 cases of tetralogy of Fallot, and 3/4 cases of truncus arteriosus, using their set of DGCR markers (HUGO chromosome 22 workshop report, Philadelphia, 1992). A somewhat less frequent incidence of hemizygosity (5%) in sporadic tetralogy of Fallot patients has been identified using the HP500 marker as a probe (Wilson Dl, et al, abstract 16, Proceedings of the British Paediatric Association Meeting, Warwick, April 1992). One problem with these studies is the subtlety of some of the extra-cardiac manifestations, that is, it is difficult to be certain one is dealing with a truly isolated cardiac defect. The frequency with which deletions are detected has been shown to increase with the incidence of noncardiac features; a recent study of the conotruncal face anomaly demonstrated the hemizygosity of HP500 sequences in each of the live cases studied (DI Wilson et al., unpublished data). This makes it dilficult to estimate the incidence of birth defects secondary to hemizygosity within 22qll. Large-scale prospective studies of non-syndromal heart-defect patients using a battery of markers across the DGCR are necessary to provide the comprehensive data needed. The combined incidence of DGS and VCFS is approximately in 1 in 10000. It is interesting to speculate on the possible causes of the variability seen in this disease. Environmental inIluences (teratogens) may have an inIluence in some cases, and it is possible that the level of transcription or gene product activity of the non-deleted locus is itself genetically determined. It is also possible that larger deletions predispose to more severe dysmorphology, and that deletions are larger in the more severely affected children of mildly affected parents. This would imply the existence

Isolation region

of genes from the DiGeorge

critical

Much of the DGCR has now been cloned in yeast artificial chromosome YAC and cosmid vectors. One previously described gene, encoding catechol-O-methyl transferase (COMT), has been mapped within the DGCR. It is unlikely that COMT plays any role in the development of the pharyngeal pouch structures, but it may be involved in some of the neurological complications, especially the psychosis reported in association with VCFS [ 28*,29]. COMT metabolizes catecholamines such as noradrenaline, adrenaline and dopamine, and has both high- and low-activity alleles. The presence of COMT activity may serve as a functional barrier for catecholamines in the brain and placenta; low COMT activity has been reported in women with primary affective disorder (disorder of mood, often involving depression). Individuals hemizygous for COMT who have a low metabolizing allele on their non-deleted chromosome might therefore be predisposed to development of the psychotic features reported in VCFS. Molecular characterization of the basis for polymorphism COMT activity is underway in several laboratories and should facilitate testing of this hypothesis. The positional cloning of genes mapping to the DGCR is in its infancy, but attempts are concentrated on identiQing genes expressed during embryogenesis. Genes isolated from relevant libraries are now being examined by tissue section in situ hybridization and related techniques [ 301. The finding that genes encoding a zinc-finger motif are mutated in some human dysmorphic syndromes, for example, Grieg’s syndrome, has prompted the search for such genes on chromosome 22. Interestingly, several such sequences have been isolated by homology screening and have been mapped to 22pter-22qll [31,32]. To date, no gene encoding a zinc-linger protein has been mapped within the DGCR. What protein might the gene or genes important for the development of the 22qll haploinsufficiencies encode? Currently, any answer would represent a guess; however, there are several lines of evidence - including teratological studies, chick embryo manipulation studies and mouse genetic models - suggesting that control of the neural crest’s contribution to development is important. Mice homozygous for a mutation of the Hoxl.5 (Hoz4.?) gene, as introduced by homologous recombination in embryonic stem (ES) cells, have many features reminiscent of DGS (see Table 2) [4]. However, this murine genetic defect is recessive, with heterozygotes completely unaffected, and the human HOXgene maps to chromosome 7.

435

436

Mammalian

genetics

Acknowledgements table

2 Comparison

syndrome

(DC9

of the abnormalities

and the Hoxl.5

gene

observed knockout

t/0x15-

Abnormal

shape

+

12 h of birth

+

body

Bloating Death Thymic

aplasia aplasia defects

+

+

+

+

+ +

arterial

tree

defects

The presence ab’sence

my research

group

and all those

who

have

collaborated

with

us over the past three years, in particular the Newcastle group. The work in my laboratory is supported by the MRC and the British Heart Foundation.

Rarely

+

+

stenosis

Abnormal Skeletal

I thank

DCS

Septation Valve

mbuse.

+ within

Parathyroid Cardiac

in DiCeorge

of an abnormal

Occasional

+

+

+

+

feature

is indicated

References

Within the next year or two many more of the genes located within the DGCR should be isolated. Evidence supporting involvement of the genes in DGS could involve the discovery of point mutations or intragenic deletions in patients, or the identification of a provocative temporal and spatial pattern of expression. Experiments involving the construction of gene-knockout mice should provide the most convincing evidence, and it is possible that certain chimeric animals will display a phenocopy of DGS; for example, given a major contribution of the donor ES cells carrying the mutated gene to the neural crest. Once such an experiment is successfully completed, it will be of interest to elucidate the function of the gene (or genes) involved, its interactions with other genes within the same developmental pathway, and hopefully the mechanisms by which haploinsufficiency can lead to such a wide range of human malformation.

reading

Papers of particular interest, published within the annual period of review, have been highlighted as: . of special interest .. of outstanding interest 1.

EMANIJEL

.2

DE IA CHAPEUE

3.

GREENBERG F, ELDER FFB, D: Cytogenetic Findings

by (+ ) and the

by ( - 1.

and recommended

BS: Molecular Cytogenetics: Towards Dissection of the Contiguous Gene Syndromes. Am J Hum Genet 1988. 43:575-578. A, HERVA R, KOM~TO M, AUIA P: A Deletion in Chromosome 22 can Cause Digeorge Syndrome. Hum &net 1981, 57:253-256. HAFFNER

P, NO~HRUP

H, LEDBETTER

in a Prospective Series of Patients with DiGeorge Anomaly. Am J Hum Genet 1988, 43&X-611.

4.

CHI~AKA 0, CAPECCHI MR: Regionally Restricted Develop mental Defects Resulting from Targeted Disruption of the Mouse Homeobox Gene Hoxl.5. Nature 1991, 350:473-479.

5.

CAREY AH, ROACH S, WILIJUSON R, DUMAMANSKI JP, NORDENSKJOID M, COUINS VP, ROULEAU G, BUN N, JALBERT P, S~AMBLER PJ: Localisation of 27 DNA Markers to Region

of Human Chromosome 22qll-pter Deleted in Patients with DiGeorge Syndrome and Duplicated in the der22 Syndrome. Genomics 1990, 7~2-306. 6.

7.

8.

FIB~SON WJ, BIJDARF M, MCDERMID H, GREENBERG BS: Molecular Studies of DiGeorge Syndrome.

F, EMANUEL

Am J Hum

Genet 1990, 46:888-895. SHARKEYAM, MCIAREN I, CARROU M, FANI-ES J, GREEN D. WIISON D, &AMBLER PJ, EVANS HJ: Isolation of Anonymous DNA Markers for Human Chromosome 22qll from a Flow Sorted Library, and Mapping Using Hybrids thorn Patients with DiGeorge Syndrome. Hum Genet 1992, 89:7378. CAREY AH, C~AU~~EN D. OAKEY H, WUSON

U, LUDECKE H-J, HOFZXHEMKE B, Ews D, BURN J, WILUAMsON R, ScAMEUR PJ:

Interstitial Deletions in DiGeorge Syndrome Detected with Microclones from 22qll. Mamm Genome 1992, 3:101-105. 9.

Conclusion

Until recently, DGS was thought to be a rare disorder with several aetiologies. It now appears that it is but one manifestation of a relatively common segmental aneusomy, hemizygosity for a region of 22qll. A number of important questions remain to be answered. How many genes are involved in haploinsticiency and what is their function? Is there any molecular basis for the varied phenotype seen between unrelated individuals and within families? What is the frequency of 22qll deletion in the genem.l population and do certain sequences within 22qll predispose to chromosome rearrangement? The progress of the international genome mapping project and advances in methods of gene analysis and disease modelling sh6uld enable us to answer these questions in the not too distant future.

SUMBLER PJ, Cm JP, NORDENSKJOLD

AH,

WIXE

RKH.

ROACH

S, DUMANSKI

M, WU.UMSON R: Microdeletions Within 22qll Associated with Sporadic and Familial DiGeorge Syndrome. Genomti 1991, 10:201-206.

10. ..

DRKOU DA, BUDARF ML, EMANUEL B: A Genetic Etiology for DiGeorge Syndrome: Consistent Deletions and Microdeletions of 22qll. Am J Hum Genet 1992, 503924-933. Confirms that submicroscopic deletions are a cause of DGS; all karyotypes assessed were of high ( > 850) bands resolution. Establishes an SRO of > 750 kb for the DGCR. RFLP studies of DGS families show that genomic imprinting is not important for generating the DGS phenotype. 11. WILSON Dl, CROSS 1, G~OLXHIP JA, S~AMBLER PJ, TAYLOR JFN, WALSH K, BURN J: Prospective Cytogenetic Study of 36 Cases of DiGeorge Syndrome. Am J Hum Genet 1992, 51:957-963. 12. CAREYAH, KEUY D, l-LUIORD S, WADEY R, WILSON D, GooDsHIP J, BURNJ, PAUL T, SHARKEYA, DUMANSKIJ, ET AL: Molecular Genetic Study of the Frequency of Monosomy 22qll in DiGeorge Syndrome. Am J Hum Genet 1992, 51~964-970. 13.

GREENBERG F, CROWDER WE, PASCHALL V, COLON-LURES J-C, L~BIANSKI B, UDBETI’ER DH: Familial DiGeorge Syndrome and

Deletions Asssociated Pardai Monosomy Chromosome Genet 1984, 65:317-319. 14.

of human

22. Am J Hum

DESMAZEC, StXhtBLER P, PRIEUR M. HMFORD S, SIDI D, LE F, AURW A Routine Diagnosis of DiGeorge Syn drome by Fluorescent In Sftu Hybridisation. Hum Genet 1992,90663-665. WORD

S,

LINDSAY

E,

NAWDU

M,

Cluw

AH,

BAID~

4 SUMBIER PJ: Low-Copy-Repeat Sequences Flank the DiGeorge/Velo-Cardio-Facial Syndrome Loci at 22qll. Hum Mol Genet 1993, 2:191-K%. Provides FISH evidence for low copy number repeat families within 22qll. The two loci detected by one cosmid are often deleted in DGS patients, indicating the large size of the commonly deleted region. Some repeats at 22qll appear to be of relatively recent evolutionaty origin. as determined by their cross-hybridization to primate sequences. .

16.

U XM, YEN PH, SHAPIROLJ: Characterization of a Low-Copy Repetitive Element S232 Involved in the Generation of Frequent Deletions of the Distal Short Arm of the X Chromosome. Nucleic Acids Res 1992, 20:1117-1122.

17.

YEN PH.

LI X-M,

TSAI S-P, JOHNSON

C, MOHANDAS

T, SHAPIRO

LJ: Frequent Deletions of the Human X Chromosome Distal Short Arm Result from Recombination Between Low-Copy Repetitive Elements. Cell 1990, 61:6036lO. 18.

19. 20.

GOIDBERG

R. MARION R, MORDERON

R, MOTZKIN

B, MARION

R, &AMBLER

PJ, SHPIUNIZEN

R: Velo-Cardio-Facial Syndrome: A Review of 120 Cases. Am J Med Genet 1993, 45:313319. 21. ..

SW\MBLER PJ, KEUY

D. WI-N

R, GOLDBERG

22.

KELLY D, GOODSHIP

23.

defects

Scambler

WILWN DI, CROSS IE, GoODsHIF’ JA COULnuw, S, CAREy AH, SCAMBIER PJ, BAIN HI-l, HUNTER AS, CARTER PE, BURN J: Dl-

Wuso~

DI, GOOD~HIP

JA

BURN J, CROSS IE, SG~BLER

PJ: De.le-

tions Within Chromosome 22qll in Familial Congenital Heart Disease. Luncet 1992, 340:573575. Reports a study of nine families with at least two members a&ted by congenital heart defects. FII fantIRes had deletions of the DGCR demonstrating that deletions within 22qll are likely to be an Important cause of familial congenital heart defect. One interesting obsetvation was that In those families with a 22qll deletion the a&ted IndIvIduals had varied anatomical defects, whereas those without a detectable deletion had anatomicaky identical malformations. 26.

WIU~ON DI, BENNFTT BRITON S, MCKEOWN 1, STROBEL S, %AMBUR PJ: An Individual

27.

KERNIT DM,

28.

SHPRI~V~ZEN RJ, GOLDBERG

C, KEUY

D, CROSS

with Naonan and DiGeorge Syndromes with Monosomy 22qll. Arch DLs child 1993, 68:187-189. Lwro~

Morphogenesis.

WM, MATTYSSE S: Genetics, Chance and Am J Hum Genet 1986, 413979-985. R, GODING-KUSHNER

KJ, MARION

RW:

Late Onset Psychosis In the Velo-Cardio-Facial Syndrome. Am J Med Genet 1992, 42:141-142. Draws attention to the occurrence of vadous psychotic presentations In adolescents and adults with VCFS. See [ 18) for further details.

.

29.

DUNHAM I, Couuus J, WADEY R, %AML%L!ZR PJ: Possible Role for COMT in Psychosis Associated with Velo-Cardio-FaciaI Syndrome. Luncet 1992, 340:1361-1362.

30.

BUDARF Druscou

31.

HEUBNER K, DRUCK T, CR~CE

32.

Diwcou. DA, SPINNER NB, BUDARF MI MCDONAU)-MCGINN PM, ZACKAI EH, GOLDBERG RB, SHPRINIZEN RJ, SAAL HM, ZUNANA J, JON= MC, ~7 AL: Deletions and Microdeletions of 22q11.2

in VCFS. Am J Med Genet 1992. 44:261-268. Cytogenetic, RFLP and quantitative Southern-blot analysis is used to detect 22qll hemixygosity in 14/15 VCFS cases; three had cytogenetIcaIIy detectable deletions. Again, as in [2l**], the deletions were detected using markers derived from the DGCR

birth

..

GOLDBERG R, WILSON D, LINDSAY E, CAREV AH, J, BURN J, CROSS 1, SHPRINIZEN R, SCAMBLER PJ:

Contirmation that the Velo-Cardio-Facial Syndrome Is Associated with Haploinsufficiency of Genes at Chromosome 22qll. Am J Med Genet 1993, 45:30%312. ..

25.

R, SHPRINIZEN

R: The Velo-CardIo-Facial Syndrome is Associated with Chromosome 22 Deletions which Encompass the DiGeorge Syndrome Locus. Luncet 1992, 339:1138-1139. Describes deletions of the DGCR in a series of VCFS patients, including those without heart defects. The study makes use of quantitative Southern-blot analysis and FISH. The SRO observed in VCFS corresponds with that of DGS.

22 and associated

George Syndrome, Isolated Aortic Coarctation and Isolated Ventricular Septai Defect In Three Sibs with a 22qll Deletion of Maternal Origin. f3r Heart J 1992, 66:308312. Describes a famiIy where four members have an interstitial deletion of 22ql1, as detected by high-resolution cytogenetics and quantkative Southern-blot analysis. The phenotype varies amongst the famiIy members, ranging from mild craniofacial dysmorphbm to severe DGS. These results have stimulated the subsequent investigation of other families exhibiting a variety of congenital heart defects.

M, WIZN~A A, SHPR~NTZEN RJ:

Phenotypic Overlap Between Velo-Cardio-Facial Syndrome (VCF) and the DiGeorge Sequence (DGS). Am J Hum Genet 1985, 37 (suppl)A54. STEVENS CA, CAREYJC, SHIGEOKA AO: DiGeorge Anomaly and Velo-Cardio-Facial Syndrome. Pediatrics 1990, 85:526530. GOIDBERG

24. .

DIE.V

15.

chromosome

ML, BAIDW~N

S, BEGEL

J, MCDERMID

H, EMANUEL BS,

D: Isolation and Characterisation of a cDNA horn 22q11.2 that Maps to the DiGeorge Syndrome Critical Region (DGCR). Am J Hum Genet 1992, 51 (suppI)All9. CM, THEBEN

H-J: Twenty-Seven

Nonoverlapping Zinc Finger cDNAs from Human T Ceiis Map to Nine Different Chromosomes with Apparent Clustering. Am J Hum Genet 1991, 48:726740. AUBRY M, MARMEAu DELATTRE 0, T~ohw GA: Cloning of Six

C, ZHANG FR, ZAHED L, FIGLEWlcz D, G, DE JONG PJ, JUUEN J-P, ROULMU New Genes with Zinc Finger Motifs

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