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Home , Campomelic dysplasia, Hypochondroplasia, Kallmann syndrome, Pseudohypoparathyroidism, Stickler syndrome, Waardenburg syndrome

I Med Genet 1994;31:507-517 507

Review article J Med Genet: first published as 10.1136/jmg.31.7.507 on 1 July 1994. Downloaded from

A gene map of congenital malformations

Andrew 0 M Wilkie, Joanna S Amberger, Victor A McKusick

Abstract process". The suggested distinction from dys- Congenital malformations frequently plasia ("an abnormal organisation of cells into arise sporadically, making it difficult to tissue(s) and its morphologic result(s)")'0 is determine whether or not they are gen- difficult to make in practice. Here we have etic in aetiology, let alone which gene(s) included macroscopically detectable, external may be involved. Nevertheless, rapid or intemal structural anomalies (including progress has been made over recent years dysmorphic facial features or growth retard- in the localisation and identification of ation), present at birth in a significant propor- gene in specific malforma- tion ( > 5%) of cases, with a provisional (P) or tions. This review draws from Mendelian confirmed (C) localisation on the human gene inheritance in man Johns Hopkins map. Metabolic disorders with anomalies de- University Press, 11th ed, 1994) and the tectable at birth (for example, mucolipidosis online version (OMIM) to catalogue 139 type II, GM1 gangliosidosis, Bloom syn- loci (including 65 specifically identified drome) are thus included in the listing, but genes) implicated in congenital malfor- non-dysmorphic conditions or those develop- mations. Some of the most interesting ing during infancy are not. Other macroscopi- recent developments are discussed. cally detectable abnormalities such as congen- ital , polycystic kidney , and (J7 Med Genet 1994;31:507-517) fetal hydrops as a result of homozygous a0 thalassaemia are included, but disorders that are subtle or only microscopically detectable Congenital anomalies contribute significantly to (for example, retinitis pigmentosa, juven- the burden of human disease; Baird et al' have ile nephronophthisis, spherocytosis) are estimated their birth incidence to be over 5%. excluded. Disorders of skin structure (for ex- http://jmg.bmj.com/ Their aetiology may be chromosomal, single ample, , hyperkeratosis, epidermo- gene, environmental, polygenic, multifactorial, lysis bullosa) are included, but those of pig- or unknown. The final three categories com- mentation (, ) are not. prise the majority, and very few "polygenes" Most chromosomal localisations classified as have yet been implicated in congenital malfor- "in limbo" (L) have been excluded, but a few mations (the association of cleft lip ± palate cases in which the evidence appears relatively

with genetic variation at the transforming strong are retained (preceded by a question on September 28, 2021 by guest. Protected copyright. growth factor-alpha locus in 2p13 is one excep- mark in table 2 and the figure). Some classic tion).2' However, considerable progress has dysmorphic syndromes (for example, Angel- been made in the identification of chromoso- man, fragile X) that are rarely associated with mal, single gene, and environmental contribu- congenital malformations and would be diffi- tions to malformation: this article summarises cult to diagnose at birth are included. current (March 1994) knowledge about those The list comprises 139 loci, including 65 disorders that have been mapped in the human specifically identified genes. In the great genome. Detailed information on each disorder majority of instances the affected infant is provided in table 1, arranged in chromosomal carries the , but in a few cases (rhesus Institute of Molecular order: the nomenclature used has recently been haemolytic disease, maternal , Medicine, John explained in this Journal.4 Table 2 presents an fetal hydantoin syndrome), the abnormality Radcliffe Hospital, Headington, Oxford alphabetical list of these disorders for ease of arises from maternal-fetal interaction (disrup- OX3 9DU, UK reference, and the figure shows their localisa- tion).10 Most identified genes encode enzymes A 0 M Wilkie tion on the map. Appropriate or structural , and have been isolated Center for Medical references may be found in McKusick's cata- using classical biochemical techniques (finc- , The Johns logue,5 together with various reviews.69 Cita- tional cloning). Notable recent progress has Hopkins University tions in this article are selective and refer to been made in elucidating the heterogeneous School of Medicine, recent or molecular 12 Blalock Building, particularly pertinent work. basis of Zellweger syndrome," Room 1007, 600 N In compiling this gene map we had some Fanconi anaemia,"3 and epidermolysis bullosa'4 Wolfe Street, difficulty in deciding which particular disorders by this approach. Although relatively few genes Baltimore, MD as "congenital malformations". have been identified by positional cloning,78 the 21287-4922, USA qualified et a as "a J S Amberger Spranger al'0 defined malformation number is accelerating rapidly. Strategies used V A McKusick morphologic defect of an organ, part of an have included a combination of genetic linkage organ, or larger region of the body resulting Correspondence to and gross chromosomalrearrangement (neuro- Dr Wilkie. from an intrinsically abnormal developmental fibromatosis type 1),chromosomal rearrange- 508 Wilkie, Amberger, McKusick

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Table 2 A gene map of congenital malformations (by disorder) Disorder Location Disorder Location 3-beta-hydroxysteroid dehydrogenase, type II, , sporadic type (2) Xpll.21 deficiency (3) lpl3.1 Juberg-Marsidi syndrome (2) Xql2-q21 -, type II (1) 12q13.1 1-q13.2 (2) Xp22.3 J Med Genet: first published as 10.1136/jmg.31.7.507 on 1 July 1994. Downloaded from (2) 4pl16.3 (1) 12ql3.1 1-q13.2 Adrenal hyperplasia, congenital, due to Langer-Giedion syndrome (2) 8q24.1 1-q24.13 1 7-alpha-hydroxylase deficiency (1) 10q24.3 Laron (1) 5pl3-pl2 Adrenal hyperplasia, congenital, due to Leprechaunism (1) l9pl3.2 21-hydroxylase deficiency (3) 6p2l .3 Lowe syndrome (3) Xq26.1 Adrenal hypoplasia, primary (2) Xp2l .3-p2l .2 , 154700 (3) 15q21.1 (2) Xp22 MASA syndrome, 303350 (2) Xq28 Alagille syndrome (2) 20pIl.2 McCune-Albright polyostotic fibrous dysplasia, Alpha-thalassemia/mental retardation syndrome, type 174800 (1) 20q13.2 1 (1) 16pter-p 13.3 Megalocornea, X-linked (2) Xq2l .3-q22 Alpha-thalassemia/mental retardation syndrome, type (2) Xql2-ql3 2 (2) Xql2-q21.31 Mental retardation, X-linked, syndromic-2, with (2) 15qll-ql3 dysmorphism and cerebral atrophy (2) XplI-q21 Anhidrotic ectodermal dysplasia (2) XqI2.2-13. 1 Mental retardation, X-linked, syndromic-4, with Aniridia-2 (3) IlpI3 congenital and low fingertip arches (2) Xq I 3-q22 Anterior segment mesenchymal dysgenesis (2) 4q28-q3 1 Mental retardation, X-linked, syndromic-5, with Atrial septal defect, secundum type (2) 6p21l.3 Dandy-Walker malformation, disease, Bardet-Biedl syndrome (2) 16q21 and (2) Xq25-q27 (2) Xq28 Mental retardation-skeletal dysplasia (2) Xq28 Basal cell nevus syndrome (2) 9q3 1 ? with linear skin defects (2) Xp22.2 Beckwith-Wiedemann syndrome (2) IIpter-pl5.4 Miller-Dieker syndrome (2) 17pl3.3 , epicanthus inversus and (2) 3q22-q23 Mucolipidosis II (1) 4q21-q23 Bloom syndrome (2) 15q26.1 VII (1) 7q21.ll Borjeson-Forssman-Lehmann syndrome (2) Xq26-q27 Multiple endocrine neoplasia IIB (3) 10qI 1.2 Branchiootorenal dysplasia (2) 8q13.3 (2) l9ql3.2-q13.3 -I (2) 1 7q24.3-q25. 1 Nail-patella syndrome (2) 9q34 Cartilage-hair hypoplasia (2) 9pl3-ql 1 Nance-Horan syndrome (2) Xp22.3-p21 .1 Cat eye syndrome (2) 22q1 1 Neonatal , 239200 (3) 3q21-q24 Cataract, Coppock-like (3) 2q33-q35 Neurofibromatosis, type I (3) 17ql 1.2 Chondrodysplasia punctata, X-linked recessive (2) Xp22.3 (3) Xpl 1.4 Cleft palate, X-linked (2) Xq2i1.1-q21.31 , 4 clinical forms, 166200, ?Cleidocranial dysplasia (2) 8q22 166210, 259420, 166220 (3) 17q2l .31 -q22.05 Coffin-Lowry syndrome (2) Xp22.2-p22. 1 Osteogenesis imperfecta, 4 clinical forms, 166200, Contractural arachnodactyly, congenital (3) Chr.5 166210, 259420, 166220 (3) 7q22.1 ?Cornelia de Lange syndrome (2) 3q26.3 Otopalatodigital syndrome, type I (2) Xq28 Craniosynostosis, type 2 (3) 5q34-q35 Pelizaeus-Merzbacher disease (3) Xq22 Craniosynostosis, type 1 (2) 7p2l .3-p2l .2 Pelviureteric junction obstruction (2) 6p ?Cutis laxa, marfanoid neonatal type (1) 7q3 1. I -q31.3 Persistent Mullerian duct syndrome (1) l9pI3.3-pl3.2 Denys-Drash syndrome (3) llpl3 Peters anomaly (2) 1 lpl3 (2) 5q31-q34 Phenylketonuria (3) 12q24. 1 DiGeorge syndrome (2) 22ql 1 Pituitary hormone deficiency, combined (1) 3pll Ehlers-Danlos syndrome, type IV, 130050 (3) 2q31 Polycystic kidney disease-I (2) 16pl3.31 Ehlers-Danlos syndrome, type VI, 225400 (1) lp36.3-p36.2 Porphyria, congenital erythropoietic (1) l0q25.2-q26.3 Ehlers-Danlos syndrome, type VIIAI, 130060 (3) 17q21 .31 -q22.05 Prader-Willi syndrome (2) 15qll Ehlers-Danlos syndrome, type VIIA2, 130060 (3) 7q22.1 Pseudohermaphroditism, male, with gynecomastia (1) 17ql2-q21 Endocardial fibroelastosis-2 (2) Xq28 , type Ia, 103580 (1) 20q13.2 Epidermolysis bullosa dystrophica, dominant, 131750 Pseudovaginal perineoscrotal hypospadias (1) Chr.2 (3) 3p21.3 Pseudo-Zellweger syndrome (1) 3p23-p22 Epidermolysis bullosa dystrophica, recessive, 226600 (3) 3p2l.3 Pyruvate dehydrogenase deficiency (1) Xp22.2-p22. 1

Epidermolysis bullosa simplex, 131900 (3) 17ql2-q21 Reifenstein syndrome (1) Xcen-q22 http://jmg.bmj.com/ Epidermolysis bullosa simplex, Dowling-Meara type, Rieger syndrome (2) 4q25-q27 131760 (3) 12ql l-ql3 Rubinstein-Taybi syndrome (2) 16pl3.3 Epidermolysis bullosa simplex, Dowling-Meara type, Saethre-Chotzen syndrome (2) 7p2l 131760 (3) 17ql2-q21 Sclerotylosis (2) 4q28-q31 Epidermolytic hyperkeratosis, 113800 (3) 12ql l-ql3 SED congenita (3) 12q13.1 1-q13.2 Erythroblastosis fetalis (1) lp36.2-p34 (2) Xpter-p22.32 Erythrokeratodermia variabilis (2) I p36.2-p34 ?Sialidosis (2) 6p21.3 Exostoses, multiple, type 1 (2) 8q24.1 1-q24.13 Simpson-Golabi-Behmel syndrome (2) Xq26 Exostoses, multiple, type 2 (2) 1 lpl2-qI 1.2 SMED, Strudwick type (1) 12q13.1 1-q13.2 Fanconi anemia-i (2) 20ql3.2-ql3.3 Smith-Magenis syndrome (2) 17pl 1.2

?Fetal hydantoin syndrome (1) lpl I-qter Split-hand/split-foot deformity, type 1 (2) 7q21.2-q21.3 on September 28, 2021 by guest. Protected copyright. (2) Xp22.31 Split-hand/split-foot deformity, type 2 (2) Xq26 (3) Xq27.3 Stickler syndrome, type I (3) 12q13.1 1-q13.2 Fukuyama type congenital muscular dystrophy (2) 9q31-q33 Supravalvular aortic stenosis, 185500 (3) 7ql1.2 Galactosemia (1) 9p13 Testicular feminization (1) Xcen-q22 Galactosialidosis (1) 20qI3.1 Thalassemias, alpha- (1) 16pter-p 13.3 Glutaricaciduria, type IIA (1) 15q23-q25 Thoracoabdominal syndrome (2) Xq25-q26.1 Glutaricaciduria, type IIB (2) Chr.19 Treacher Collins mandibulofacial dysostosis (2) 5q32-q33. 1 Glutaricacidemia, type IIC (3) 4q32-qter Trichorhinophalangeal syndrome, type I (2) 8q24.12 GMI-gangliosidosis (1) 3p21-pl4.2 -I (2) 9q33-q34 Goeminne TKCR syndrome (2) Xq28 Tuberous sclerosis-2 (2) 16pl3.3 Gonadal dysgenesis, XY type (1) Ypl 1.3 (2) 1q32 Greig cephalopolysyndactyly syndrome (3) 7pl3 Velocardiofacial syndrome, 192430 (2) 22ql1 Gustavson syndrome (2) Xq26 , type I (3) 2q35 Heterotaxy, X-linked visceral (2) Xq25-q26 Waardenburg syndrome, type III, 148820 (3) 2q35 Hirschsprung disease (3) 10ql 1.2 , 193520 (3) 17ql 1.2 Holoprosencephaly-3 (2) 7q36 Wieacker-Wolff syndrome (2) Xql3-q21 ?Holoprosencephaly-1, alobar (2) 18pter-ql 1 Williams-Beuren syndrome, 194050 (3) 7q1.2 ?Holoprosencephaly-2, alobar or semilobar (2) 2p21 Wilms tumor (3) lipI3 Hydrocephalus due to aqueductal stenosis, 307000 (3) Xq28 Wolf-Hirschhorn syndrome (2) 4p16.3 (2) 4pl16.3 Wrinkly skin syndrome (2) 2q32 Hypophosphatasia, infantile, 241500 (3) 1p36. I-p34 Zellweger syndrome-I (2) 7ql 1.23 Ichthyosis, X-linked (3) Xp22.32 Zellweger syndrome-2 (1) 1 p22-p2l Incontinentia pigmenti, familial (2) Xq27-q28 Zellweger syndrome-3 (3) 8q21.1 512 Wilkie, Amberger, McKusick .0

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ment alone (Wilms tumour/Denys-Drash syn- is even more complex, including paternal dupli- drome), or a "positional candidate" approach cations, maternal inversions, segmental pater- (Waardenburg syndrome type 1, aniridia, X nal isodisomy owing to somatic recombination, linked hydrocephalus'5). maternally inherited mutations, and abnormal J Med Genet: first published as 10.1136/jmg.31.7.507 on 1 July 1994. Downloaded from Over the next few years, integration of the expression of imprinted genes.26 A unifying flood of information generated by the Human theory of causation has been proposed.27 Genome Project with the characterisation of Conversely, a diverse range of distinct important developmental genes in Drosophila, can arise from different mutations mice, and other organisms will greatly increase of a single gene. This is particularly well illus- the power of the "positional candidate" ap- trated by the type 2 gene COL2A1. proach8 to identify the molecular basis of mal- in which mutations of this gene have formation. Increasingly, initial chromosomal been described include Stickler and Wagner localisation of rare disorders may become the syndromes, spondyloepiphyseal dysplasia con- major bottleneck in identifying disease genes. genita, Kniest dysplasia, achondrogenesis, and Classical genetic linkage analysis is difficult in precocious osteoarthritis. The pre- autosomal dominant congenital malformations sumably depends on the precise mutation and, (owing to the reduced fitness of affected per- in at least one case, its presence only in sons), except where penetrance is variable; in- form.28 Several genes have been implicated in deed, myotonic dystrophy is the only such both congenital malformation and neoplasia, disease gene to have been isolated by a "pure" the phenotype depending on the timing (germ- linkage approach, without the availability of a line or somatic) and/or precise nature of the candidate gene or large genomic rearrange- mutation. Such combined "teratogenes"/onco- ment.'6 On the other hand, this approach is genes (or tumour suppressor genes) include readily applied to X linked disorders, explain- PAX3 (Waardenburg syndrome/alveolar rhab- ing the much higher density of mapped genes domyosarcoma), RET (Hirschsprung disease, on the X chromosome. Linkage analysis for multiple endocrine neoplasia type 2B/medull- autosomal recessive diseases, although more ary carcinoma29), and WT1 (Denys- difficult, is feasible,'7 and there have been no- Drash syndrome/Wilms tumour), illustrating table recent successes in localising the genes for that similar developmental pathways control some rare malformations (diastrophic dyspla- cellular growth and differentiation in the em- sia,'8 cartilage-hair hypoplasia,'9 Bardet-Biedl bryo and adult. syndrome20). The identification of rare, but In a small number of cases the characteristic consistent chromosomal rearrangements in phenotype may arise from the deletion or dupli- congenital malformations9 has been instrumen- cation of two or more closely adjacent genes. tal in localising many disease loci (Prader-Willi, Examples of such "contiguous gene syn- Angelman, Rubinstein-Taybi, Williams,2' dromes"30 include the WAGR complex in DiGeorge/velocardiofacial syndromes, and llpl3, the occurrence of type II oculocuta-

campomelic dysplasia); the importance of per- neous albinism in some cases of Prader-Willi http://jmg.bmj.com/ forming a karyotype in every child with con- and Angelman syndromes,3' and, probably, the genital malformations cannot be overstated. association of supravalvular aortic stenosis with A promising, but currently largely unproven, mental retardation and characteristic beha- alternative method for identifying genes in hu- vioural changes in Williams syndrome.2' man malformation may arise from the produc- The identification of disease loci and genes in tion of an increasing number of defined mouse congenital malformations may have a number mutants by targeted gene knockout. Analysis of of practical benefits. It enables more specific on September 28, 2021 by guest. Protected copyright. the murine phenotype may suggest equivalent diagnosis, prognosis, carrier testing, and pre- human disorders that could be tested for muta- natal prediction. In some of the recessive meta- tions of the homologous gene. Although pre- bolic diseases, it paves the way for possible gene vious experience cautions that the murine and therapy, although most congenital malforma- human phenotypes will not always be recogni- tions are unlikely to benefit from this approach. sably similar,22 natural mouse mutants have Particularly important in the diagnostic context already been helpful in the identification of is the discovery that certain regions of the several human disease genes.23 In at least one genome (notably 15ql1-ql3, l7pl1.2, and case (multiple pituitary deficiency owing to 22ql 132) seem especially prone to deletions. PITI mutation24), this provided the sole means The development of fluorescence in situ of identification. hybridisation (FISH) as a routine diagnostic Investigation of the genetic basis of malfor- tool is making possible a new generation of mations has brought to light some fundamental genetic tests for suspected dysmorphic and/or concepts. Angelman syndrome arises by de malformation syndromes.33 novo maternal deletion of chromosome 15q1 1- q13, uniparental paternal disomy for the entire AOMW is grateful to the Wellcome Trust for financial support. , or an inherited mutation origi- nating from the maternal grandfatherx5: all these mechanisms reflect a difference in the 1 Baird PA, Anderson TW, Newcombe HB, Lowry RB. maternal and paternal contributions to gene Genetic disorders in children and young adults: a popula- activity in the 15qll-ql3 segment (genomic tion study. Am J Hum Genet 1988;42:677-93. 2 Ardinger HH, Buetow KH, Bell GI, Bardach J, Van Demark imprinting), so that absence of a normal mater- DR, Murray JC. Association of genetic variation of the nal gene gives rise to the condition. The range transforming growth factor-alpha gene with cleft lip and palate. Am J Hum Genet 1989;45:348-53. of mechanisms affecting the 1 lpter-p15.4 seg- 3 Holder SE, Vintiner GM, Farren B, Malcolm S, Winter ment to cause Beckwith-Wiedemann syndrome RM. Confirmation of an association between RFLPs at the A gene map of congenital malformations 517

transforming growth factor-alpha locus and non-syndro- founder populations: diastrophic dysplasia in Finland. mic cleft lip and palate. J Med Genet 1992;29: Nature Genet 1992;2:204-1 1. 390-2. 19 Sulisalo T, Sistonen P, Hastbacka J, et al. Cartilage-hair 4 McKusick VA, Amberger JS. The morbid anatomy of the hypoplasia gene assigned to chromosome 9 by linkage human genome: chromosomal location of mutations caus- analysis. Nature Genet 1993;3:338-41. ing disease (update 1 December 1993). J Med Genet 20 Kwitek-Black Carmi et AE, R, Duyk GM, al. Linkage of J Med Genet: first published as 10.1136/jmg.31.7.507 on 1 July 1994. Downloaded from 1994;31:265-79. Bardet-Biedl syndrome to chromosome 16q and evidence 5 McKusick VA. Mendelian inheritance in man, 11th ed. Balti- for non-allelic heterogeneity. Nature Genet 1993;5:392-6. more: The Johns Hopkins University Press, 1994. 21 Ewart AK, Morris CA, Atkinson D, et al. Hemizygosity at 6 Wilson GN. Genomics of human dysmorphogenesis. Am J the elastin locus in a developmental disorder, Williams Med Genet 1992;42:187-96. syndrome. Nature Genet 1993;5:1 1-16. 7 Collins FS. Positional cloning: let's not call it reverse any 22 Harlow E. For our eyes only. Nature 1992;359:270-1. more. Nature Genet 1992;1:3-6. 23 Darling SM, Abbott CM. Mouse models of human single 8 Ballabio A. The rise and fall of positional cloning? Nature gene disorders. I. Non-transgenic mice. BioEssays Genet 1993;3:277-9. 1992;14:359-66. 9 Tommerup N. Mendelian cytogenetics. Chromosome re- 24 Tatsumi K, Miyai K, Notomi T, et al. Cretinism with arrangements associated with mendelian disorders. JT Med combined hormone deficiency caused by a mutation in the Genet 1993;30:713-27. PITI gene. Nature Genet 1992;1:56-8. 10 Spranger J, Benirschke K, Hall JG, et al. Errors of morpho- 25 WagstaffJ, Knoll JHM, Glatt KA, Shugart YY, Sommer A, genesis: concepts and terms. J Pediatr 1982;100:160-5. Lalande M. Maternal but not paternal transmission of 11 Shimozawa N, Tsukamoto T, Suzuki Y, et al. A human gene 15ql 1-13-linked nondeletion Angelman syndrome leads to responsible for Zellweger syndrome that affects peroxi- phenotypic expression. Nature Genet 1992;1:291-4. some assembly. Science 1992;255:1132-4. 26 Weksberg R, Shen DR, Fei YL. Song QL, Squire J. Disrup- 12 Gartner J, Moser H, Valle D. Mutations in the 70K peroxi- tion ofinsulin-like growth factor 2 imprinting in Beckwith- somal membrane gene in Zellweger syndrome. Wiedemann syndrome. Nature Genet 1993;5:143-50. Nature Genet 1992;1:16-23. 27 Junien C. Beckwith-Wiedemann syndrome, tumourigenesis 13 Strathdee CA, Gavish H, Shannon WR, Buchwald M. and imprinting. Curr Opin Genet Dev 1992;2:431-8. Cloning of cDNAs for Fanconi's anaemia by functional 28 Winterpacht A, Hilbert M, Schwarze U, Mundlos S, complementation. Nature 1992;356:763-7. Spranger J, Zabel BU. Kniest and Stickler dysplasia 14 Fuchs E, Coulombe PA. Of mice and men: genetic skin phenotypes caused by collagen type II gene (COL2AI) diseases of keratin. Cell 1992;69:899-902. defect. Nature Genet 1993;3:323-6. 15 Rosenthal A, Jouet M, Kenwrick S. Aberrant splicing of 29 van Heyningen V. One gene - four syndromes. Nature neural cell adhesion molecule LI mRNA in a family with X 1994;367:319-20. linked hydrocephalus. Nature Genet 1992;2:107-12. 30 Schmickel RD. Contiguous gene syndromes: a component of 16 Brook JD, McCurrach ME, Harley HG, et al. Molecular recognizable syndromes. J Pediatr 1986;109:231-41. basis of myotonic dystrophy: expansion of a trinucleotide 31 Rinchik EM, Bultman SJ, Horsthemke B, et al. A gene for (CTG) repeat at the 3' end of a transcript encoding a the mouse pink-eyed dilution locus and for human type II protein kinase family member. Cell 1992;68:799-808. . Nature 1993;361:72-6. 17 Lander ES, Botstein D. Homozygosity mapping: a way to 32 Wilson DI, Goodship JA, Burn J, Cross IE, Scambler PJ. map human recessive traits with the DNA of inbred Deletions within chromosome 22ql 1 in familial congenital children. Science 1987;236:1567-70. heart disease. Lancet 1993;340:573-5. 18 Hastbacka J, de la Chapelle A, Kaitila I, Sistonen P, Weaver 33 Ledbetter DH. The 'colorizing' of cytogenetics: is it ready A, Lander E. Linkage disequilibrium mapping in isolated for prime time? Hum Mol Genet 1992;1:297-9. http://jmg.bmj.com/ on September 28, 2021 by guest. Protected copyright.