Table Of ContentMENDELIAN INHERITANCE IN MAN
CATALOGS OF AUTOSOMAL DOMINANT,
AUTOSOMAL RECESSIVE, AND
X-LINKED PHENOTYPES
Victor A. McKusick
William Heinemann Medical Books Ltd.
London
Copyright © 1966 by The Johns Hopkins Press
Baltimore, Maryland 21218
Printed in the United States of America
Library of Congress Catalog Card Number 66-23005
To my wife, Dr. Anne B. McKusick
FOREWORD
These catalogs had their inception in 1960 when, in connection with an inquiry into
the genetics of the X chromosome, it seemed advisable to examine the question 4 'What
genetic information is carried by the X chromosome?" The catalog of X-linked traits in
man was first published in 1962 (McKusick, 1962A,B). Two categories of traits were
included—those for which X-linkage was considered proven and those for which the
evidence is in various degrees suggestive but not conclusive. All traits, rare and common,
were included.
In 1962 a study of genetic disorders in Old Order Amish communities was initiated.
The question then arose ' 'What rare recessive disorders might one expect to encounter
in inbred groups such as these?" Inbred populations afford an opportunity to detect
"new" rare recessive phenotypes in man. A catalog of known recessive phenotypes
would obviously be useful in recognizing these. The catalog of récessives was confined
mainly to rare phenotypes, that is to say, those which in outbred populations have a
homozygote frequency of 1 in 1,000 or less.
By 1963 the complexity of the récessives catalog prompted exploration of computer
methods for assembling, revising, and indexing.
In 1964 a catalog of dominant phenotypes was undertaken—with some hesitation
because of the magnitude of the undertaking and the questionable status of a large
number of traits for which "dominant inheritance with incomplete penetrance" is
suggested. Again the catalog was confined mainly to uncommon traits. "Uncommon"
was, however, not precisely defined so that some morphologic traits were included.
Furthermore, anomalous hemoglobins, red cell antigenic types, leukocyte types, and
serum protein types—co-dominant traits—were included.
Two classes of entries have been made in each of the three catalogs. In the case of
those marked with an asterisk, the particular mode of inheritance is, in the writer's
opinion, quite certain, according to the criteria outlined below. In the case of the others,
the suggestions of the particular mode of inheritance are judged to be sufficiently
strong to warrant inclusion, and it is considered important that these less certain items
be included so that further families will be studied as they come to attention.
Each entry consists of three parts: (l)the preferred designation, (2) a brief description
of the phenotype, with a resume of genetic information, and (3) key references. In the
case of récessives, manifestations, by special test or otherwise, in hétérozygotes are
usually listed. An attempt has been made to select references which are up to date
and/or have particularly useful discussions of the genetics.
The definitions of dominant and recessive used in the preparation of these catalogs
are those given by Mendel: "... those characters which are transmitted entire, or
almost unchanged in the hybridization, and therefore in themselves constitute the char-
acters of the hybrid, are termed the dominant, and those which become latent in the
process recessive." Following Mendel, care has always been taken to use the terms
"dominant" and "recessive" as attributes of a character, i.e., a phenotype, and to
have a specific phenotype in mind. The question is, then, whether the specific phenotype
is observed in the hétérozygote or only in the homozygote. Depending on the answer,
the specifically defined trait is considered dominant or recessive, respectively.
Many of the phenotypes for which a particular mode of inheritance is indicated as
proved might not meet criteria which experimental geneticists would be likely to lay
down. A rare phenotype transmitted through several successive generations in a family
VII
viii without consanguinity, affecting both males and females and transmitted by both males
and females, with male-to-male transmission, is considered autosomal dominant. In
the case of a rare phenotype affecting brothers and sisters with normal parents but with
instances of parental consanguinity, recessive inheritance has usually been considered
very likely. If the phenotype was shown to result from an enzyme deficiency and espe-
cially if both parents showed by test a partial deficiency, then recessive inheritance
was considered proved. In the case of oroticaciduria, this was the case even when only
one homozygote had been observed. Pedigrees with multiple affected males in two or
more sibships connected through females were taken as evidence of X-linked recessive
inheritance. Pedigrees with a dominant pattern in which among the offspring of affected
males all daughters but no sons were affected were taken as evidence of X-linked domi-
nant inheritance. The diagnosis of X-linkage is discussed in more detail in my mono-
graph "On the X Chromosome of Man." Certainly X-linked dominant traits may be
mistakenly labeled autosomal dominant, and in early stages when only a few cases are
known, X-linked recessive inheritance may suggest autosomal recessive inheritance.
The confusion of X-linked inheritance with male-limited autosomal dominant inheri-
tance, when affected males do not reproduce, was also discussed in the monograph
mentioned above.
For both applied and scientific reasons I have considered it worthwhile to invest very
considerable effort in assembling these catalogs. The reasons, in addition to those
already listed, include the following:
1) Genetic counseling and the management of hereditary problems demand accurate
diagnosis and familiarity with the experience reported in the literature. Genetic hetero-
geneity—fundamentally distinct hereditary entities which are phenotypically similar-
is often not taken into account adequately in connection with genetic counseling.
2) Genetic disorders give us insight into the normal. These catalogs of hereditary
traits are like photographic negatives from which a positive picture of man's genetic
constitution can be made. For example, the fact that agammaglobulinemia and classic
hemophilia are X-linked disorders tells us that the X chromosome carries loci concerned
with the synthesis of gamma globulin and of antihemophilic factors. As complete know-
ledge as possible of the normal genetic constitution of man is bound to be useful in the
long run. Physicians have a unique opportunity to contribute to knowledge of what
Lewontin referred to as "man's mutational repertoire."
The numerology of these catalogs is of interest from several points of view. The ratio
of autosomal dominants to autosomal recessive is of note: 837 dominants to 531 ré-
cessives.* A few years ago the preponderance of dominants was even greater, but ad-
vances in biochemical genetics in the last few years have added many new items to the
list of récessives while fewer new dominants have been added. In experimental species
such as the mouse, récessives predominate. This difference between man and mouse
is due largely to a difference in mating patterns. Most mutations are recessive. In closely
mated mice they are likely to come promptly to attention. In outbred man, however, a
recessive mutation can occur and the gene be lost, either by chance or because of a
disadvantage in the hétérozygote, without ever "meeting up with itself" in a homo-
zygote. Or if a homozygote occurs, it may, because of the small size of human families,
be an isolated case and may not be recognized as representing a distinct genetic entity.
The catalog of X-linked traits represents the largest number of loci which has been
identified on one chromosome in any metazoan, excepting Drosophila. Since 68 loci on
the X chromosome have been identified and since the X chromosome represents about
6 per cent of the length of the haploid set of chromosomes, one would expect that
about 900 autosomal loci would be known. In fact less than 600 are confidently known.
♦These figures refer to all items. The corresponding figures for established (asterisked) items
are 269 dominants and 237 récessives. In the X-linkage catalog, 119 items are listed, of which 68
are asterisked.
The main deficiency is undoubtedly in the group of récessives. An X-linked recessive ix
behaves as a dominant in the male. It is, for practical purposes, always expressed if
the male has the gene. The number of X-linked dominants is close to what one would
expect from the number of autosomal dominants and from the length of the X chromo-
some relative to that of the autosomal complement.
The total number of loci identified by these catalogs is a very small proportion of the
total number of genes. Estimates of the number of genes in man have taken two ap-
proaches: (a) From the measured amount of DNA, and assuming a triplet code and 150
amino acids per polypeptide chain, one concludes that there is enough DNA to code
for about ten million polypeptide chains. A multistranded state of the chromosomes
would, of course, reduce this number, (b) From the relatively extensive information
on E. coli it is concluded that several thousand genes would be required to code for
all the proteins of the cell. Because of the greater complexity of any multicellular orga-
nism, especially man, as many as 100 times as many genes may be present. Probably
the total number of genes in man is not less than 100,000. Thus the catalogs reveal
only a small portion, perhaps only 1 per cent of the whole.
3) Among the uses to which the catalogs may be put is "deletion mapping" of the
chromosomes. Observation of a specific autosomal recessive disorder in a patient
with the cri du chat syndrome (deletion of the short arm of a chromosome in the 4-5
group) would, for example, provide evidence on thecartography of the particular genetic
locus. An example of deletion mapping has been provided by Elmore and his colleagues
(1965).
4) The mode of inheritance can be a useful guide in the search for the basic defect in
genetic disorders. Thanks to the margin of safety with which most enzyme systems are
endowed, a gene-determined enzyme deficiency is likely to be reflected in the pheno-
type only in the homozygote. Contrariwise, when the mutation concerns a non-enzyme
protein, e.g., a structural protein like collagen, it is plausible to presume that change in
the amino acid sequence might alter the physical properties in such a way as to be reflect-
ed in the phenotype, even though only half the particular protein is of the mutant type.
All inborn errors of metabolism (defined in the strict Garrodian sense) are récessives.
I believe one would be wasting his time to look for an enzyme defect in the Marfan
syndrome, a dominant. Obviously there is much more to biochemical genetics than
merely the determination of the amino acid sequence of proteins and the matter of
whether these proteins are enzymes or non-enzymes. (Speculation here about genetic
control mechanisms in man of the Jacob-Monod type and the genetic behavoir to be
expected of mutations in various of these mechanisms would be useless.) Nonetheless
the generalization stated above is probably true. In recessive disorders an enzyme
defect (or a defect in a peptide hormone like the growth hormone; see ateleiotic dwarf-
ism) should be sought. In dominant disorders, abnormality in a non-enzymic protein
is more likely.
In assembling these three catalogs, consideration had constantly to be given to
heterogeneity, which is often discovered when a genetic disorder is examined closely;
what at first is thought to be one entity is found to be several clinically similar (i.e.,
phenotypically similar) but fundamentally (i.e. genotypically) distinct disorders. Ex-
amples are numerous.
The principles of genetics force one to think in terms of specific mutation as a specific
etiologic mechanism resulting in a specific disease entity. In 1930, Knut Faber, pro-
fessor of medicine in Copenhagen, produced a monograph entitled Nosography in which
he traced the development of understanding about the classification of disease. To
Gregor Mendel's principles he assigned a leading role in directing thought along lines
of specific entities. The one other factor of comparable impact was the advent of the
Bactériologie Era with its focus on specific etiology and specific entities. One has but to
recall that it was only a little over a century ago that in many circles jaundice, dropsy,
x anemia, fever, and so on, were thought of as entities, to realize the influence of bac-
tériologie and genetic discoveries on the conceptual basis of medicine.
In medical genetics there is little place for expressions such as "spectrum of disease,"
"disease A is a mild form, or a variant, of disease B," and so on. They are either the
the same disease, if they are based in the same mutation, or they are different diseases.
Phenotypic overlap is not necessarily any basis for considering them fundamentally
the same or closely related. For example, diagrams purporting to show the interrelation-
ship of neurologic diseases (Myrianthopoulos ei a/., 1964) are totally meaningless,
and useless except as an indication of phenotypic overlap.
What methods are available for demonstrating heterogeneity of genetic disease in
man? These can be outlined as follows:
Recognition of Heterogeneity in Genetic Disease of Man
I. Genetic methods
A. Mode of inheritance, e.g., spastic paraplegia
B. Non-allelism of récessives, e.g., deaf-mutism
C. Linkage relationships, e.g., elliptocytosis
II. Analysis of phenotype, e.g., the mucopolysaccharidoses
III. Biochemical analysis, e.g., the hereditary non-spherocytic hemolytic anemias
IV. Physiologic studies, e.g., the X-linked hemophilias
An experience much less frequent in medical genetics than discovery of heterogeneity
is demonstration of affinity, i.e., that phenotypes which appear at first to represent
separate entities are in fact the result of one and the same genotype. It is fair to say
that there are no completely established examples, although we might point to Wilson's
disease, which can present in young patients as an essentially pure hepatic disorder
and in older patients as a predominantly neurologic disorder. Familial Mediterranean
fever may have the picture of primary amyloidosis throughout its course without ever
displaying the picture of episodic fever and polyserositis. In man final proof of genetic
identity depends on demonstrating precisely the same chemical change at the molecular
level. (See amaurosiscongenita of Leber,typel,fora possible example of genetic affinity.)
The value of maintaining these catalogs on magnetic tape lies in the ease of revision
and republication. It is planned to maintain the catalogs on a continuing basis and to
republish whenever justified by the accumulation of new material.
It is difficult to master genetic nosology in every branch of medicine and difficult to
maintain an overview of all medical literature. Quite aside from honest differences of
opinion regarding the classification of some phenotypes and the interpretation of the
evidence on modes of inheritance, errors may have crept in and important omissions
may exist. I have no illusions of either the infallibility or the completeness of these
catalogs. I will appreciate suggestions for increasing the usefulness of the catalogs
and would like to have errors and omissions called to my attention.
The Johns Hopkins Hospital Victor A. McKusick, M.D.
June, 1966
References
Elmore, S. M. Nance, W. E., McGee, B. J., Engel-de Montmollin, M. and Engel, E.:
f
Pycnodysostosis, with a familial chromosome anomaly. Am. J. Med. 40: 273-282, 1966.
McKusick, V. A.: On the X chromosome of man. Quart. Rev. Biol. 37: 69-175, 1962A.
: A catalog of X-linked traits in man. J. génét. hum. 11: 51-64, 1962B.
: On the X Chromosome of Man. Washington: Am. Inst. Biol. Sei., 1964.
Myrianthopoulos, N. C, Lane, M. H., Silberberg, D. H. and Vincent, B. L.: Nerve con-
duction and other studies in families with Charcot-Marie-Tooth disease. Brain 87:
589-608, 1964.
ACKNOWLEDGMENTS
I am indebted to a very large number of colleagues in Baltimore and elsewhere for assis-
tance in assembling these catalogs. First I would mention the research fellows whom I
have been privileged to have in my group since 1960 when the X-linked catalog was first
initiated. In the second place I have been assisted greatly by the advice of many of my
colleagues in the Johns Hopkins University who are much more familiar with some
specialized areas than am I. Colleagues elsewhere who have reviewed the catalogs at
one stage or another include Alexander G. Beam, New York City; A. Donald Merritt,
W. DeMyer, and Wolfgang Zeman, Indianapolis; J. A. Fraser Roberts, London; Margery
W. Shaw, Ann Arbor; John M. Opitz, Madison; George Fraser, formerly London, now
Adelaide; P. E. Becker, Gronignen; Arno G. Motulsky, Seattle; Herbert A. Lubs, Jr.,
New Haven; Mette Warburg, Copengahen; David J. Weatherall, Liverpool, and many
others, who I hope will forgive my failure to mention them by name. None of the errors
in these catalogs can be laid to any of the above, but without their help these catalogs
would be much less authoritative. Computerization was possible through the sympa-
thetic and ingenious assistance of Drs. Robert P. Rich and Richard H. Shepard of the
Johns Hopkins Computing Center and was executed in the Division of Medical Genetics
by David R. Boiling and his staff. Miss Sheila Manning provided able bibliographic
assistance.
Some aspects of the process of assembling the catalogs were supported by an NI H
Genetics Training Grant (GM 795) and by an NIH Research Grant entitled "Mapping the
Chromosomes of Man" (GM 10189).
xi
General Sources
In assembling these catalogs, several general sources, specialized monographs, and
textbooks were used.
The older literature was reviewed in the following:
Gates, R. R.: Human Heredity. New York: Macmillan, 1946 (2 vols.).
Sorsby, A. (ed.): Clinical Genetics. St. Louis: C. V. Mosby, 1953.
Touraine, A.: L'hérédité en médecine. Paris: Masson, 1955.
The older literature is also usefully surveyed in The Treasury of Human Inheritance
(1909-1958), a series of reviews of the literature on a variety of genetic disorders: hemo-
philia, diabetes insipidus, dwarfism, angioneurotic edema, brachydactyly, polydactyly,
osteogenesis imperfecta, Leber's optic atrophy, color blindness, retinitis pigmentosa,
congenital stationary night blindness, multiple exostoses, cleidocranial dysostosis,
Huntington's chorea, peroneal muscular atrophy, hereditary ataxias, spastic paraplegia,
pseudohypertrophic muscular dystrophy, myotonic dystrophy, Lau re nee-Moon syn-
drome. The Treasury is a publication of the Galton Laboratory, London (Cambridge
University Press). Contributors of reviews include Julia Bell, Percy Stocks, William
Bulloch, and Paul Fildes, the largest proportion having been done by Bell.
Comparably encyclopedic works of more recent publication include the following:
Becker, P. E. (ed.): Humangenetik. Ein kurzes Handbuch in fünf Bänden. Stuttgart:
G. Thieme, 1964 (and later).
Gedda, L. (ed.): De genetica medica. Rome: G. Mendel Institute, 1961-1962 (6 vols.)
The medical genetics literature for the six years 1958-1963, inclusive, was surveyed by
my colleagues and me in annual reviews published in the Journal of Chronic Diseases
and collected as follows:
McKusick, V. A., and colleagues: Medical Genetics 1958-1960. St. Louis: C. V. Mosby,
1961.
McKusick, V. A., and colleagues: Medical Genetics 1961-1963. Oxford: Pergamon
Press, 1966.
Exceedingly useful in reviewing those forms of hereditary disease on which bio-
chemical information is fullest was the following:
Stanbury, J. B., Wyngaarden, J. B. and Fredrickson, D. S. (eds.): The Metabolic Basis
of Inherited Disease. New York: Blakiston Division, McGraw-Hill, 1966 (2nd ed.).
The following journals were drawn on heavily:
American Journal of Human Genetics
Journal of Heredity
Annals of Human Genetics (and its predecessor Annals of Eugenics)
Ada genetica et statistica medica
Journal of Medical Genetics
Journal de génétique humaine
Ada geneticae medicae et gemellologiae
Eugenics Quarterly
The current literature has been surveyed with the assistance of Current Contents
(a weekly publication of the table of contents of medical and genetic periodicals) and
Excerpta Medica abstracts on human genetics.
Specialty monographs used in assembling the catalogs included the following:
I. Eye
Duke-Elder, S.: System of Ophthalmology. III. Normal and abnormal development.
Part 2. Congenital deformities. St. Louis: C. V. Mosby, 1963. VIM. Diseases of the
Outer Eye. Parti. Conjunctiva. Part 2. Cornea. St. Louis: C. V. Mosby, 1965.
Franceschetti, A., François, J. and Babel, J.: Les hérédo-dégénérescences chorio-
rétiennes (dégénérescences tapéto-rétiennes). Paris: Masson, 1963 (2 vols.).
xv
xvi François, J.: Heredity in Ophthalmology. St. Louis: C. V. Mosby, 1961.
: Congenital Cataracts. Springfield, III.: Charles C Thomas, 1963.
Waardenburg, P. J., Franceschetti, A. and Klein, D.: Genetics and Ophthalmology.
Springfield, III.: Charles C Thomas, 1961 (Vol. 1) and 1963 (Vol. 2).
Walsh, F. B.: Clinical Neuro-ophthalmology. Baltimore: Williams and Wilkins, 1957.
II. Skin
Butterworth, R. and Strean, P.: Clinical Genodermatology. Baltimore: Williams
and Wilkins, 1962.
Cockayne, E. A.: Inherited Abnormalities of the Skin and Its Appendages. London:
Oxford University Press, 1933.
III. Nervous System
Allen, N.: Developmental and degenerative diseases of the brain, Chapter 5, in Farmer,
T. W.: Pédiatrie Neurology. New York: Hoeber Medical Division, Harper & Row,
1964.
Blackwood, W. and others: Greenfield's Neuropathology. Baltimore: Williams and
Wilkins, 1963.
Ford, F. R.: Diseases of the Nervous System in Infancy, Childhood, and Adolescence.
Springfield, III.: Charles C Thomas, 1960.
Rëfsum, S.: Genetic aspects of neurology. Chapter 49, in Baker, A. B. (ed.): Clinical
Neurology. New York: Hoeber Medical Division, Harper & Row, 1962 (2nd ed.).
IV. Muscle
Adams, R. D., Denny-Brown, D. and Pearson, C. M.: Diseases of Muscle. New York:
Harper & Row, 1962 (2nd ed.).
V. Hand malformations
Temtamy, S.: Genetic Factors in Hand Malformations. Ph.D. thesis. Johns Hopkins
University, 1966.
VI. Genetic Disorders of the Skeleton and of Connective Tissue in General
McKusick, V. A.: Heritable Disorders of Connective Tissue. St. Louis: C. V. Mosby,
1966 (3rd ed.).
Rubin, P.: The Dynamic Classification of Bone Dysplasias. Chicago: Year Book
Medical Publishers, 1963.
