Nature Genetics
24, 203 - 204 (2000)
doi:10.1038/73389
Ellis-van Creveld syndrome and the AmishVictor A McKusickInstitute of Genetic Medicine, Johns Hopkins Hospital
, Baltimore, Maryland 21287, USA
.
mckusick@peas.welch.jhu.edu Genetic studies often involve the cooperation of large numbers of
affected persons and their families. The discovery of the gene that, when
mutated, causes a form of dwarfism (Ellis-van Creveld syndrome) has been accelerated
through a collaborative effort between geneticists and the Old Order Amish,
of Lancaster County, Pennsylvania.As described on pages 283−286 of this issue, Judith Goodship and
a multi-national group of collaborators1 have identified the
gene that is mutated in people with a form of dwarfism, Ellis-van Creveld
(EvC) syndrome. They discovered five different mutations, including one that
underlies the disorder in the Old Order Amish. Originally described in 1940
(ref. 2) by paediatricians Richard Ellis and Simon
Van Creveld, EvC syndrome is an autosomal recessive disorder, involving postaxial
polydactyly of the hands (see figure),
short stature with shortening especially of the forearms and lower legs and,
in at least half of all cases, congenital heart malformation.
The mutation in the Amish of Lancaster County, Pennsylvania, in whom the
disorder occurs at unprecedentedly high frequency, is predicted to cause aberrant
splicing. It occurs in the fifth nucleotide of intron 13 of a novel gene,
EVC, that is predicted to encode a protein containing a leucine zipper,
three putative nuclear localization signals and a putative transmembrane domain.
The pathogenic 'status' of the Amish mutation is supported by
the fact that mutation of analogous nucleotides effect disease: according
to the Human Gene Mutation Database3, 144 intronic mutations,
causing a total of 81 separate disorders, have been reported at the +5 position
of introns.
Of history and heritage
The Amish have several characteristics4,
5 that recommend
them to medical geneticists. First, they are descended from a limited number
of founders who immigrated, during the eighteenth century, to the United States
from the Rhineland (in the southwest of Germany) where they had settled temporarily
following emigration in the 1690s from the Canton of Berne, Switzerland. Second,
the Amish observe strict endogamy (they marry only within the community),
with gene flow being exclusively centrifugal (that is, members may leave the
community but 'outsiders' do not join it and thereby introduce
exogenous genes). Third, like the Icelanders, they keep excellent genealogic
records and have a restricted geography. Finally, they tend to have large
families, with many children.
It was therefore possible to trace the lineage of both parents of all 50
EvC cases back to a single couple, Samuel King and his wife (regrettably,
her name is no longer known), who immigrated4 to Eastern Pennsylvania
in 1744—thus demonstrating founder effect and a recessive pattern of
inheritance. Epidemiological data indicate that the frequency of the mutated
gene is approximately 0.066 and that heterozygotes make up about 12.3% of
the population6. At the time of these estimates, 12.6% of Lancaster
County Amish carried Samuel King's surname, and Samuel was the only male founder
of that name.
During studies carried out in the mid-sixties5,
7, it became
apparent that the Amish are distributed in three consanguineal kin groups8 (demes) across the United States. At that time, each was made up
of about 14,000 members. The deme in Lancaster County was founded by those
who immigrated before the American Revolution. The deme of Holmes County (Ohio),
and the deme comprised of groups in Lagrange and Elkhart Counties (Northern
Indiana) descended, for the most part, from post-revolutionary immigrants
who, upon finding the land taken up in Eastern Pennsylvania, moved to points
west.
The genetic distinctness of the three major demes is supported by different
patterns of blood-group frequencies9,
10, different family names—23%
of people in the Lancaster deme have the name Stoltzfus, which is absent in
the other demes—and different frequencies of rare recessive disorders.
For example, EvC syndrome was found to be limited to the Lancaster-County
deme. Haemophilia B, on the other hand, was (and still is) unusually frequent
in the Holmes-County deme, and almost completely limited to that group. It
is as though the Amish immigrants were streaked like bacteria on a culture
plate across the waist of America, with the genetic profile of each deme depending
on the genetic constitution of the founders, for whom the present populations
represent a bioassay.
Cartilage-hair hypoplasia
A second recessive form of dwarfism, distinct from EvC, is prevalent in
the Lancaster-County deme11. Cartilage-hair hypoplasia (CHH)
was previously unrecognized until the Amish came to the attention of clinical
geneticists in the mid-sixties. In contrast with EvC syndrome, it occurs in
all Amish demes. Moreover, it is impossible to trace its origin to a single
founder couple, indicating that the mutation was introduced by several immigrants.
It turns out that CHH is also frequent in Finland12; the odds
favour a mutation of independent origin with respect to that carried by the
Amish—albeit one that has achieved a high frequency through the same
mechanisms: founder effect and perhaps genetic drift. Whereas the 'causative'
gene's locus is known13, its identity yet eludes the assiduous
efforts of positional cloners in Helsinki and Bethesda.
After discovery of CHH in the Amish, rare cases of CHH were recognized
in non-Amish. For example, Billy Barty, an actor and founder of Little People
of America, a support group for persons of short stature, has CHH. So did
Michael ('Pat') Bilon, who played ET in the movie of that name.
Medical genetics is indebted to the Amish for their cooperation in studies
that have led to an improved understanding of genetic disorders. The physicians
who carried out the studies in the 1960s and 70s approached the Amish with
a view to helping them. Arrangements were made, for example, for surgical
repair of the cardiac defect in EvC patients and for orthopedic correction
of their knee deformities. Aid was also provided to family members with non-EvC
related problems of great diversity. How could knowledge of the Amish 'EvC'
mutation help? Pre-marital and pre-natal counselling should now be possible,
based on testing for the splice-site mutation or a nearby marker—ideally
one within the gene. Goodship and colleagues discovered a polymorphism that
is in linkage disequilibrium with the 'causative' mutation, and
could therefore serve as such a marker.
Whether the Amish would acquiesce to premarital testing is uncertain, and
it is unlikely that they would accept prenatal testing because of the implication
of abortion. Because a specific EVC mutation is limited to the Lancaster
County Amish, marriage between an EvC carrier with an Amish from another community
might be recommended but may generate logistical difficulties. Alternatively,
knowledge of carrier status could inform choice of partner within the Lancaster
County Amish community.
The Amish acceptance of the geneticists was achieved by their being introduced
by local physicians and by sociologists whom they trusted. The relationships
were maintained through communication with the bishops and others in authority
and by the assistance of Amish who served as guides and introducers during
home visits. Another notable example of beneficial collaboration between geneticists
and religous community is that between the Ashkenazi Jewish groups who use
screening for mutations that cause Tay-Sachs disease as the basis of marriage
advice by rabbis.
The EvC syndrome in the Amish has become a favourite elementary genetics
textbook example of several aspects of human genetics. Now, to founder effect,
consanguinity, recessive inheritance and so on, one can add linkage mapping,
positional cloning and the molecular nature of mutation, as well as carrier
detection and the social implications thereof. Possibly, it will not be long
before the student can be informed of the way in which the mutation disturbs
development, leading to polydactyly, heart defect and skeletal dysplasia.
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