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 mutations 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 cataract, polycystic kidney disease, 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, ichthyosis, hyperkeratosis, epidermo- gene, environmental, polygenic, multifactorial, lysis bullosa) are included, but those of pig- or unknown. The final three categories com- mentation (albinism, piebaldism) 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 mutation, but in a few cases (rhesus Institute of Molecular order: the nomenclature used has recently been haemolytic disease, maternal phenylketonuria, 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 human genome map. Appropriate or structural proteins, and have been isolated Center for Medical references may be found in McKusick's cata- using classical biochemical techniques (finc- Genetics, 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 c-C 1-1 0. C '. .0 .00. >1 C) o S. P U U n -S D4 :+ - _/ _S U, 00 N N - -_ -_ J Med Genet: first published as 10.1136/jmg.31.7.507 on 1 July 1994. Downloaded from C) _ _ 0 0 10'0>1 '-'0 (A C.- Q 0. C) .0li C> a C)4 co 0CG o(> C) 0 -C)00 Q co U 0 E . *0 N .N ° C) 0 0.bo 5~v C)Cu oaG e9z=00 0 oJo 00Cu0XW- C) :> 04,D Q 0~ ° Et. S_= o 0C 0Cu) C).beCq G 4L Cu lCC0.C) .00 0.0 g.4 g0. E, C) sO 0c 0 co '0 < <'0 '0 «< OW44 Q~44 Cu. 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