Short reports

Journal of Medical Genetics 1988, 25, 634-637

Linkage analysis of manic
depression in an Irish family
using H-ras 1 and
INS DNA markers
Manic depression (bipolar affective disorder) is one of the
major psychiatric illnesses. It is distinguished from
unipolar major depression by the occurrence of manic
episodes, symptoms of which show a variable combination
of heightened and expansive mood, restlessness,
irritability, pressure of speech, disinhibition, increased
energy, and grandiose ideas or delusions. It has a lifetime
risk of slightly less than 1% in most populations studied. A
large genetic component has been shown using twin and
adoption studies.

Egeland et all have shown linkage between the manic
depressive phenotype in one North American pedigree and
two polymorphic DNA markers on the tip of the short arm
of chromosome 11. Other studies2 ' have failed to show
this linkage in Icelandic and other North American
pedigrees.
We have ruled out tight linkage between these DNA

markers and the manic depressive phenotype, assuming
that the disorder is segregating as an autosomal dominant
trait in a large Irish pedigree. A single, unilateral source of
the manic depression is likely but cannot be proven.
The diagnoses were based on the Research Diagnostic

Criteria of Spitzer et al,4 compiled using a combination of
interviews, a review of the case notes, and the
Schizophrenia and Affective Disorders Schedule-Lifetime
Version (SADS-L).

All cases were of bipolar affective disorder, apart from
one case of unipolar depression. Of the unaffected subjects
only those over the age of 55 were used to minimise the
risk of false negative phenotype assignment. The pedigree
is shown in the figure.
DNA samples from members of the pedigree were

Received for publication 18 November 1987.
Revised version accepted for publication 28 January 1988.

digested with the restriction enzymes PvuII and Sacd. They
were separated by electrophoresis on agarose gels and
transferred to nylon membranes. Hybridisations were
carried out with the DNA probes H-ras 1 to Sacd digests
and INS to PvuII digests. Both of these loci show high
frequency restriction fragment length polymorphisms
owing to the insertion or deletion of short, repeated DNA
sequences (variable tandem repeats). The resulting
genotypes are shown in the figure.
Lod scores were calculated using the computer program

LIPED and the results are presented in the table. These
data exclude the possibility of close linkage between manic
depression and the chromosome 11 markers H-ras 1 and
INS, under the assumption that there is an autosomal
dominant gene responsible for the disorder in this family.
This would indicate that the gene or genes responsible for
manic depression in this family are at other, as yet
unknown, loci. Further work is needed to identify other
manic depressive gene loci in this and other pedigrees.
Isolation and examination of these genes will lead to a
better understanding of the pathogenesis of the disease and
its interactions with the environment.

MICHAEL GILL*, PATRICK McKEoNt,
AND PETER HUMPHRIES*

*Department of Genetics, Trinity College Dublin; and
tDepression and Manic Depression Research Unit,

St Patrick's Hospital, Dublin, Ireland.

72706 6765 60 58 5655

ABBCAB BC BCAB AB BC BC BC BC AC
14 1 1 14 11 114 13 11 14 11 23

25

AB BB AB
14 1 1 13

FIGURE Pedigree of family showing age, H-ras 1 alleles
(A,B,C), and INS alleles (1,2,3,4).

TABLE Lod scores calculated between the two marker loci, H-ras I and INS, and the manic depression phenotype, for
various values of recombination fraction (0), using three selected penetrance values for the susceptible genotypes (AA and
Aa); 085 was the maximum penetrance of the susceptible genotype found in the Amish study' and 0-63 was the average
penetrance found in their sample.

Penetrance Recombination frequencY 0

0 00 0-001 0-002 0-005 0-025 0-050 0-100 0-300

H-ras 1 1-00 -x -5 40 -4-80 -4(00 -2 51 -1-76 -0-93 -0-02
0-85 -x -4 66 -4(06 -3-26 -1-85 -1-25 -0-66 -0-03
0-63 -x -4-44 -3-84 -3 06 -1-70 -1-14 -0-62 -0 06

INS 1-00 -x -2 70 -2 40 -2-01 -1-31 -1-02 -0-73 -0-17
0-85 -x -2-69 -2-39 -2-0(0 -1-30 -1I00 -0-67 -0-14
0-63 -xc -2-67 -2-38 -199 -1-28 -0 96 -0-63 -0-11

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Short reports

References

Egeland JA, Gerhard DS, Pauls DL, et al. Bipolar affective
disorders linked to DNA markers on chromosome 11. Nature
1987;325:783-7.

2 Hodgkinson S, Sherrington R, Gurling H, et al. Molecular
genetic evidence for heterogeneity in manic depression. Nature
1987;325:805-6.

3 Detera-Wadleigh SD, Berettini WH, Goldin LR, Boorman D,
Anderson S, Gershon ES. Close linkage of c-Harvey-ras-1 and
the insulin gene to affective disorder is ruled out in three North
American pedigrees. Nature 1987;325:806-8.
Spitzer RL, Endicott J, Robins E. Research diagnostic criteria:
rationale and reliability. Arch Gen Psychiatr 1978;35:773-82.

Correspondence and requests for reprints to Dr M
Gill, Department of Genetics, Lincoln Place Gate,
Trinity College, Dublin 2, Ireland.

Prenatal diagnosis of mosaicism
for del(18)(q12*2q21*1) and a
normal cell line
A 37 year old single Hispanic woman had amniocentesis
because of maternal age. She had had five pregnancies,
resulting in two normal children with a previous partner,
one elective abortion, and one tubal ectopic pregnancy
with the present 20 year old partner. The medical and
family histories were unremarkable.
Two separate primary amniotic fluid cell cultures at

21 weeks' gestation showed mosaicism for 46,XY/46,XY,
del(18)(q12-2q21-1)(fig 1). Six of 25 cells (24%) from one
primary culture and eight of 25 cells (32%) from the other
primary culture showed the deletion. The chromosomes of
the parents were normal.
The pregnancy was electively terminated by prosta-

glandin at 24 weeks' gestation. The fetus weighed 740 g (at
about the 50th centile). Noted were the following cranio-
facial anomalies: high and narrow forehead, long philtrum,
small and thin lips especially the lower (fig 2), long and
broad thumbs, contractures at the middle interphalangeal
joints, bilateral transverse palmar creases, long and broad
big toes, and long toes. Necropsy showed a large foramen

q21 1

FIG 1 Partial GTG banded karyotype from an amniotic
fluid cell. The arrows indicate the breakpoints in the normal
chromosome 18 (left) and in the idiogrammatic 18 (right).
The dark band q12-3 and some ofthe light staining band
q21-1 are deleted in the anomalous chromosome 18.

Received for publication 9 June 1987.
Revised version accepted for publication 10 August 1987.

FIG 2 Thefetus at24 weeks.

ovale that was indistinguishable from an atrial septal
defect.
The deletion was found in 24% (6/25) of cultured cells

from amniotic fluid, in 2% (1/50) of cells from cord blood,
and in 47% (35/75) of cells from umbilical cord tissue
obtained at the time of pregnancy termination.

Since this pregnancy, the couple has had another
pregnancy resulting in a normal son.

Mosaicism for a structural anomaly at prenatal diagnosis
is an uncommon event, occurring in only 15 of about
60 000 genetic amniocenteses.' Since de Grouchy et al2
first described a syndrome associated with partial deletion
of the long arm of chromosome 18, several other physical
anomalies associated with deletion of 18q122-2*q21-1
have been described.3 This deletion was found in a
proportion of cells from the present fetus, who showed
some craniofacial features similar to those of the child
previously reported, including a high and narrow forehead
and long philtrum. The deletion responsible for this case is
more proximal than the deletion associated with
de Grouchy syndrome, which appears to involve 18q21
(probably q21-3).

We thank Mr William Herbert who participated in the
patient's care. Partial support was provided by US Public
Health, Maternal and Child Health Services, Grant
No 286.

MIRIAM G WILSON AND MING S LIN
Genetics Division, Department of Pediatrics,

University of Southern California School of Medicine,
and Los Angeles County- University of Southern California

Medical Center, Los Angeles, California, USA.

References

Hsu LYF, Perlis TE. United States survey on chromosome
mosaicism and pseudomosaicism in prenatal diagnosis. Prenat
Diagn 1984;4:97-130.

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