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Prenatal diagnosis of Fukuyama type congenital muscular dystrophy in eight Japanese families by haplotype analysis using new markers closest to the gene

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American Journal of Medical Genetics 77:310–316 (1998)
Prenatal Diagnosis of Fukuyama Type Congenital
Muscular Dystrophy in Eight Japanese Families By
Haplotype Analysis Using New Markers Closest to
the Gene
Kayoko Saito,1* Eri Kondo-Iida,1 Yukiko Kawakita,1 Du Juan,1 Kiyoko Ikeya,1 Makiko Osawa,1
Yukio Fukuyama,1 Tatsushi Toda,2 Masao Nakabayashi,3 Tomoko Yamamoto,4 and
Makio Kobayashi4
1
Department of Pediatrics, Tokyo Women’s Medical College, Tokyo, Japan
Laboratory of Genome Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan
3
Perinatal Division, Maternal and Perinatal Center, Tokyo Women’s Medical College, Tokyo, Japan
4
Department of Pathology, Tokyo Women’s Medical College, Tokyo, Japan
2
We conducted prenatal diagnosis by haplotype analysis, using newly developed microsatellite markers, in eight Fukuyama type
congenital muscular dystrophy (FCMD)
families. In addition to six new families, two
previously reported families were reexamined by haplotype analysis including
detection of an ancestral founder haplotype
(138–183–301) for 3 microsatellite markers
closest to the FCMD gene, designated
D9S2105–D9S2107–D9S172, the distances of
which from the FCMD gene are presumed to
be ∼140, ∼20, and ∼280 kb, respectively. Five
fetuses from five families were diagnosed as
nonaffected, and were subsequently confirmed to be healthy. Three fetuses of the
other three families were diagnosed as having a high probability of being affected by
FCMD. In the prenatal diagnosis conducted
for these eight families, the ancestral founder allele was observed in 13 of 16 (81%)
FCMD-bearing chromosomes. Detection of
the ancestral haplotype facilitated achieving accurate prenatal diagnosis of FCMD.
The brains of all three fetuses prenatally diagnosed as FCMD-affected showed the initial stage of cortical dysplasia, strong evidence of FCMD. Am. J. Med. Genet. 77:310–
316, 1998. © 1998 Wiley-Liss, Inc.
Contract grant sponsor: Ministry of Health and Welfare of Japan; Contract grant numbers: 8A-2, 8A-3; Contract grant sponsor: Ministry of Education, Science, and Culture, Japan; Contract
grant number: 07670906.
*Correspondence to: Dr. Kayoko Saito, Department of Pediatrics, Tokyo Women’s Medical College, 8-1 Kawadacho, Shinjuku,
Tokyo 162, Japan. E-mail: kayoko-saito@amy.hi-ho.ne.jp
Received 12 September 1997; Accepted 10 February 1998
© 1998 Wiley-Liss, Inc.
KEY WORDS: prenatal diagnosis; Fukuyama type congenital muscular dystrophy (FCMD); haplotype analysis; ancestral
founder allele; cortical dysplasia
INTRODUCTION
Fukuyama type congenital muscular dystrophy
(FCMD), first reported by Fukuyama et al. [1960] and
designated MIM 253800 in the McKusick catalog
[McKusick et al., 1994], is the most common congenital
muscular dystrophy in Japan [Fukuyama et al., 1981,
1996]. The incidence is 6.9–11.9/100,000 [Fukuyama
and Ohsawa, 1984], and the incidence ratio of Duchenne muscular dystrophy to FCMD is 2.1:1, based on
a multi-institutional study [Fukuyama et al., 1981].
The FCMD phenotype is characterized by dystrophic
changes in the skeletal muscle and CNS migration disturbances, principally cerebral and cerebellar cortical
dysplasia. The clinical manifestations are recognized in
early infancy as psychomotor retardation with hypotonia and weakness. Peak motor function, in most patients, is no better than sitting without help or sliding
along the floor on the buttocks. Brain malformations
include agyria, pachygyria, and polymicrogyria. On the
surface of the cerebral cortex, polymicrogyria and
cloudy, thickened leptomeninges are apparent. There
are three patterns of cellular migration disturbance in
the cerebral and cerebellar cortex, as reported by
Takada et al. [1984], which are observable even in the
23-week-old FCMD fetal brain [Takada et al., 1987].
The cellular migration disturbance is the origin of the
gyrus malformation characteristic of FCMD.
FCMD is an autosomal recessive genetic defect, and
the sib recurrence rate is 25% [Osawa, 1978; Fukuyama and Ohsawa, 1984]. In an effort to elucidate the
Prenatal Diagnosis of FCMD
pathogenesis of FCMD, molecular genetic analysis has
been undertaken. Toda et al. [1993] located the FCMD
gene at 9q31-q33 by a genetic linkage analysis. Furthermore, the FCMD gene was localized within a region of ∼5 cM between D9S127 and D9S2111 (CA246)
[Toda et al., 1994], based on homozygous mapping and
recombination mapping. Toda et al. [1994] also found
evidence for linkage disequilibrium between FCMD alleles and D9S306 (mfd220), the latter being located in
the FCMD candidate gene region. We previously reported prenatal diagnosis of FCMD in two families using these microsatellite markers [Kondo et al., 1996].
Toda et al. [1996] have since developed new microsatellite markers, D9S2105, D9S2107, and D9S172, the
distances of which from the FCMD gene are presumed
to be ∼140, ∼20, and ∼280 kb, respectively. These investigators indicated that most FCMD-bearing chromosomes were derived from a single ancestral founder
in Japanese FCMD patients and emphasized the value
of precisely diagnosing FCMD in order to ascertain the
ancestral haplotype, because 75% of FCMD patients
had the haplotype for D9S2105–D9S2107–D9S172,
while control individuals did not. In this report we confirmed their data by detecting the ancestral haplotype
in FCMD-bearing chromosomes compared with control
chromosomes.
Though the FCMD gene has not yet been isolated
and the gene product remains unknown, prenatal diagnosis of the disease is now possible due to advances
in the molecular genetic tools used to study FCMD.
Herein, we describe prenatal diagnosis in eight FCMD
families by haplotype analysis using the aforementioned newly developed microsatellite markers,
D9S2105, D9S2107, and D9S172, closest to the FCMD
gene. In addition to six new families, two previously
reported families were re-examined by the haplotype
analysis.
MATERIALS AND METHODS
Subjects
Eight at-risk pregnancies from eight unrelated families (Families A to H) with at least one child afflicted
with FCMD were studied. In Families A and B, examinations with the newly developed microsatellite markers were conducted to confirm our previous results [Kondo et al., 1996], the associated clinical findings of
which were described previously. The diagnosis of
FCMD in propositi was confirmed by us based on clinical findings, such as hypotonia, diffuse muscle weakness, and wasting since early infancy; facial muscle
involvement; joint contractures; delay in psychomotor
and speech development; high creatine kinase titers;
gyrus abnormalities and demyelination on CT scan or
MRI; and dystrophic change affecting muscle fibers
with proliferation of perimysial connective tissue. For
prenatal diagnosis of the eight pregnancies, fetal materials were obtained by mid-trimester amniotic fluid
sampling in seven (Families A to F and H) and by chorionic villus sampling (CVS) in one (Family G). After
the actual procedure, as well as the safety aspects and
risks, had been explained and the confidentiality of all
results guaranteed, these eight families expressed
311
their eagerness to utilize prenatal diagnosis. We obtained approval from the Intramural Ethical Committee, and this procedure was carried out according to the
Prenatal Diagnosis Guidelines of the Japan Society of
Human Genetics.
Prenatal Diagnosis Procedures
DNA was extracted from peripheral blood leukocytes
of parents and siblings. In Family F, DNA was obtained from a frozen muscle specimen, because the propositus was deceased. Fetal materials were obtained by
CVS and amniocentesis at 10 and 15–17 gestational
weeks, respectively. DNA was extracted from the chorionic villi or amniocytes. Haplotypes of family members and fetuses were determined at D9S2105,
D9S2107, and D9S172 loci [Toda et al., 1996]. The parents were informed of the results at 12–19 gestational
weeks.
Haplotype Analysis: Allele Typing
We used the markers D9S2105 [Toda et al., 1996],
D9S2107 [Toda et al., 1996], and D9S172 [Gyapay et
al.,1994], as well as D9S127 [Lyall et al., 1992],
D9S306 (mfd 220) [Weber, 1993], and D9S2111
(CA246) [Toda et al., 1995] which were mapped previously to chromosome 9q31-q33 [Toda et al., 1994].
Primer sets for polymerase chain reaction (PCR) amplification of these markers were synthesized. Conditions for PCR and subsequent electrophoresis were as
previously described [Toda et al., 1993, 1994, 1996].
PCR was performed in 25 ml reaction volumes containing 20 ng of genomic DNA, 20 pmol of one unlabeled
primer and 20 pmol of one primer end-labeled with 1.0
mCi of [g-32P]ATP using T4 polynucleotide kinase, 1×
PCR buffer (16.6 mM NH4SO4, 67 mM Tris-HCl, pH
8.8, 10 mM b-mercaptoethanol, 6.7 mM EDTA), 10%
(v/v) dimethyl sulfoxide, 1.5 mM of each dNTP, 5 mM
MgCl 2 , and 1.25 U of Taq DNA polymerase. For
D9S127, D9S306, and D9S2111, samples were incubated in a DNA thermocycler (Perkin Elmer Cetus,
Norwalk, CT) for 35 cycles under the following conditions: 94 °C for 1.5 min, 55 °C for 2 min, and 72 °C for
1.5 min. For D9S2105, D9S2107, and D9S172, samples
were incubated for 38 cycles. The first denaturation
and final elongation steps were extended to 3 and 10
min, respectively. The PCR products were analyzed on
6% polyacrylamide gel and visualized by autoradiography.
Detection of Ancestral Haplotype in FCMD
Patients and Control Individuals
To confirm the existence of linkage disequilibrium
and the ancestral founder haplotype (138–183–301 for
D9S2105–D9S2107–D9S172), haplotype analyses were
done in 39 FCMD patients (78 FCMD-bearing chromosomes), including the 8 probands, for prenatal diagnosis. The results were compared with those of 66 normal
chromosomes from FCMD parents. Alleles from the 78
FCMD-bearing chromosomes and the 66 control chromosomes were classified according to the size of PCR
products for the microsatellite DNA markers.
312
Saito et al.
Neuropathological Analysis of the Fetuses
Aborted fetuses of Families B, C, and E were autopsied at 20, 18, and 17 gestational weeks, respectively.
The brains were fixed in 10% buffered formalin 40–60
min after termination of the pregnancy. Sections were
stained with hematoxylin and eosin (HE) and periodic
acid–methanamine–silver (PAM) stain.
RESULTS
Detection of Ancestral Haplotype in FCMD
Patients and Normal Chromosomes From
Their Parents
First, we examined haplotypes of FCMD chromosomes from 39 FCMD patients at three of the closest
loci, D9S2105, D9S2107, and D9S172. The results were
compared with 66 normal chromosomes from FCMD
parents in 33 families, i.e., one each normal chromosome of their homologs 9 (Table I). Sixty (77%) of 78
FCMD-bearing chromosomes carried the ancestral
haplotype, while the same haplotype was seen in one of
66 normal chromosomes from FCMD parents. The remaining 18 chromosomes of the patients had haplotypes that may originate from previous recombinations
within the ancestral haplotype, and 7 such chromosomes were found in the parents. Other haplotypes
were observed in the remaining 58 normal chromosomes but were not seen in any of the FCMD-bearing
chromosomes.
Prenatal Diagnosis
We conducted prenatal diagnosis of FCMD in eight
families with at least one FCMD patient. In Families A
and B, the examination with the three new markers
was done to confirm the previous results [Kondo et al.,
1996] (Fig. 1). In Family A, the fetus had a paternally
derived haplotype which did not carry the FCMD gene
mutation, while the other haplotype derived from the
mother carrying the mutation, which did not show a
crossover. The ancestral haplotype, 138–183–301, was
observed on both chromosomes of the propositus (Fig.
1, A-II-2). The fetus was confirmed to be nonaffected by
showing that the ancestral haplotype was derived only
from the mother. The baby showed no signs of FCMD
after birth. She is now 3 years old and healthy.
TABLE I. Haplotypes Associated With FCMD and
Normal Chromosomes
Haplotype
No. of chromosomes
D9S2105–D9S2107–D9S172
FCMD
Controla
138–183–301
138–183–297
130–183–295
138–183–291
134–183–301
138–183–295
139–183–297
130–183–297
138–193–301
140–183–301
Others
Total
60 (77%)
6
4
2
1
1
1
1
1
1
0
78
1
0
1
0
0
0
0
1
1
4
58 (88%)
66
a
Normal chromosomes from FCMD parents.
In Family B, the fetus inherited a paternal haplotype
carrying the mutation. On the maternal chromosome, a
crossover was identified between loci D9S2105 and
D9S2111. The propositus (Fig. 1, B-II-3) and the fetus
showed the ancestral haplotype on his both chromosomes. The fetus in Family B was demonstrated to
have FCMD [Yamamoto et al., 1996].
In Family C, the fetus had both paternal and maternal chromosomes carrying the mutation and was thus
homozygous, like the propositus (Fig. 2, C-II-1). The
fetus was considered to have a high probability of having FCMD. The paternal chromosome showed the ancestral haplotype, while the maternal chromosome
showed a haplotype of 138–183–297. The parents decided to terminate the pregnancy at 18 gestational
weeks, and the fetus was neuropathologically demonstrated to have FCMD [Yamamoto et al., 1997].
In Family D, the fetus had a paternally derived ancestral haplotype that carried the FCMD gene mutation, while the other allele derived from the mother did
not have the FCMD gene mutation. The fetus was diagnosed as nonaffected, and the pregnancy was continued. The baby girl was confirmed to be healthy at 2
months of age by one of the authors (K.S.).
In Family E, both children, two boys, were afflicted
with FCMD. The fetus was diagnosed as having a high
probability of FCMD, because the haplotype was the
same as those of the elder brothers, showing homozygosity for the ancestral pattern (138–183–301). The
parents decided to terminate the pregnancy at 17 gestational weeks.
In Family F, the fetus had a paternally derived haplotype which did not carry the FCMD gene mutation,
while the other chromosome derived from the mother
carried the mutation and also showed the ancestral
haplotype. The fetus was diagnosed as nonaffected.
The baby girl was confirmed to be healthy at 3 months
of age by one of the authors (K.S.).
In Family G, the paternal haplotype of the fetus carried the FCMD gene mutation, while the maternal haplotype did not. The paternal haplotype (134–183–301)
was not the ancestral one. The fetus was diagnosed as
nonaffected. The baby boy was confirmed to be healthy
by a pediatrician at another hospital.
In Family H, the propositus was homozygous for the
ancestral haplotype. The fetus had neither the ancestral haplotype nor the affected alleles. We diagnosed
the fetus as nonaffected, and a healthy girl was born.
In these eight families seeking prenatal diagnosis,
the results indicated that 13 (81%) of 16 FCMDbearing chromosomes shared an ancestral haplotype.
Neuropathological Analysis of the Fetuses
In Family B, the parents opted for an abortion at 20
gestational weeks. On macroscopic observation of the
fetal brain, multiple small granular protrusions, up to
0.5 mm in diameter over the cerebral surface, were
noted [Kondo et al., 1996]. Histopathologically, thick
extracortical lesions, consisting of neuronal nodules,
were detected. In Family C, on macroscopic observation
of the brain from the 18-week-old fetus, the granular
protrusions were smaller and much less numerous
Prenatal Diagnosis of FCMD
313
Fig. 1. Upper: Eight-locus genotypes from members of the two pedigrees previously described [Kondo et al., 1996]. D9S306 (mfd220) was the closest
marker available at that time. Crossover was observed in the fetal haplotype in each family. Lower: Six-locus genotypes from members of the two
pedigrees. D9S2107 is the closest marker. In Family A, the fetus had a paternally derived wild-type allele which did not have the FCMD gene mutation,
while the maternally derived chromosome carried the mutant allele, which did not show a crossover. The ancestral 138–183–301 haplotype for D9S2105–
D9S2107–D9S172 was observed on both chromosomes of the propositus. In Family B, the fetus inherited a paternal haplotype carrying the mutation. On
the maternal chromosome, a crossover was identified between loci D9S2105 and D9S2111. The propositus and the fetus showed the ancestral haplotype
(138–183–301) on both their chromosomes. Each allele is shown according to PCR product sizes. Shaded and unshaded columns depict the regions
carrying the mutant and wild-type FCMD alleles, respectively. The ancestral 138–183–301 haplotype is highlighted by the white square.
than on the brain from the Family B fetus (Fig. 3a).
Microscopically, there were small but numerous defects of the basal lamina observed by PAM staining.
Neurites, glia, and granular cells were seen to erupt
through defects into the leptomeninges (Fig. 3b). The
17 week abortus of Family E was also examined pathologically. On gross examination, small granular protrusions, a characteristic of the FCMD fetal brain, were
seen (Fig. 4a). Microscopically, the linear structure
stained with PAM showed irregular disruption. The
pathological change was milder, presumably due to the
earlier gestational age (Fig. 4b). Thus, the initial stage
of cortical dysplasia was observed in these 17-, 18-, and
20-week-old fetuses, diagnosed as FCMD prenatally,
and was milder at early gestational ages.
DISCUSSION
We conducted molecular genetic analyses, for the
purpose of prenatal diagnosis, in eight FCMD families
with at least one child afflicted with FCMD, carefully
considering the ethical issues in each case. As a result,
the fetuses in five families were diagnosed as being
nonaffected, and all proved to be healthy after birth.
Those in the other three families were revealed to be
affected; the parents opted for abortion, and all three
were confirmed to have FCMD by autopsy.
In Families A and B, we used the microsatellite
markers, including D9S306 [Kondo et al., 1996]. The
analysis using this marker revealed a crossover in the
fetal haplotype in each family. Thus, the possibilities of
FCMD were 1% and 86% in Families A and B, respectively [Kondo et al., 1996]. The distance of D9S306
from the FCMD locus was presumed to be 1 Mb. We
then conducted haplotype analysis using three new
markers, D9S2105, D9S2107, and D9S172, the distances of which from the FCMD gene were estimated to
be ∼140, ∼20, and ∼280 kb, respectively [Toda et al.,
1996]. These markers revealed no crossover in Family
A. In Family B, we diagnosed the fetus to be affected by
demonstrating the fetus as having the same haplotypes
as the affected sibling except for D9S2111. We identified a crossover between loci D9S2105 and D9S2111.
As the D9S2107 and D9S172 alleles in the mother were
homozygous, they were uninformative haplotypes and
it was difficult to determine whether a crossover was
314
Saito et al.
Fig. 2. Six-locus genotypes from members of the six most recent pedigrees. In Families C and E, the fetuses had both paternal and maternal
chromosomes carrying the mutation and were thus homozygous, like the propositus. The paternal chromosome in Family C and both the paternal and
maternal chromosomes in Family E showed the ancestral haplotype (138–183–301). The fetus was considered to have a high probability of having FCMD.
In Families D, F, and G, the fetuses had a haplotype consistent with heterozygosity for the FCMD gene mutation, while the fetus of Family H was
homozygous for the normal chromosome. All four fetuses were diagnosed as nonaffected. The ancestral haplotype was observed in one or both chromosomes of the propositus.
present in these regions. However, in the maternal
chromosome of the fetus, a crossover was assumed to
have occurred between the D9S172 and D9S2111 loci,
not between D9S2105 and D9S2107 or between
D9S2107 and D9S172, because the distance between
D9S172 and D9S2111 was much longer than that between D9S2105 and D9S172 [Toda et al., 1996; Miyake
et al., 1997]. Thus, the fetal haplotype revealed homozygosity for the ancestral haplotype (138–183–301 for
D9S2105–D9S2107–D9S172). This homozygosity also
provided strong evidence that the fetus had FCMD.
Whether FCMD occurs in populations of nonJapanese ethnicity, or is strictly limited to the Japanese, is an important issue which has yet to be resolved. FCMD is very rare outside Japan; only three
patients from two Chinese (Taiwanese) families have
been diagnosed as having FCMD [Jong et al., 1994].
The population of Japan has long been isolated genetically by geography, language, and culture. The isolation and population expansion have allowed Japan to
develop a distinctive pattern of single-gene disorders,
such as FCMD. The existence of the ancestral founder
allele as the population-specific mutant allele has significance for understanding the origin of genetic disease and also provides opportunities for the detection
of FCMD-specific alleles in an at-risk population. Toda
et al. [1996] examined the rate of the ancestral haplotype, and we added the FCMD cases and control subjects described herein. We found the rate of FCMDbearing chromosomes carrying the ancestral haplotype
to be 60 (77%) of 78 chromosomes, while Toda et al.
[1996] obtained a rate of 84 (75%) of 112 chromosomes.
The rates in control chromosomes in our study and
theirs were one (1.5%) of 66 and 0 (0%) of 87, respectively. The frequency of one control chromosome having the 138–183–301 haplotype is equal to a value calculated from each allele frequency (0.1765 × 0.5185 ×
0.2571 4 0.0235) [Toda et al.,1996; unpublished data:
allele frequency of allele 138 for D9S2105 was 18/102
4 0.1765; allele 183 for D9S2107 was 56/108 4 0.5185;
allele 301 for D9S172 was 27/105 4 0.2571]. Thus, 2%
of normal chromosomes may show the same haplotype
as the ancestral founder haplotype. In these eight families seeking prenatal diagnosis, the founder haplotype
was observed in 13 (81%) of the 16 FCMD-bearing chromosomes from the propositi. In other words, confirming
the diagnosis in each propositus and determining
whether the fetuses had FCMD were facilitated, because there was at least one founder haplotype in each
of these eight FCMD families.
Prenatal Diagnosis of FCMD
315
Fig. 3. a: Macroscopic appearance of the Family C fetal brain at 18
gestational weeks. The granular protrusions were seen on the brain from
the Family B fetus. b: Microscopically, there were small but numerous
defects of the basal lamina. Neurites, glia, and granular cells were seen to
erupt through defects into the leptomeninges (PAM ×250).
In addition, crossover was seen in Families B and G
between D9S172 and D9S2111, but was not problematic, because there was no crossover between the three
microsatellite markers, D9S2105, D9S2107, and
D9S172, and D9S2111 is approximately 3 cM apart
from D9S172.
The 17-, 18-, and 20-week-old fetuses, diagnosed as
FCMD prenatally, were examined neuropathologically.
Multiple small granular protrusions over the cerebral
surface were composed of aberrant neuroglial clusters.
As judged by microscopic examination, the neurites,
granular cells, and glia migrated out through the discontinuous pial–glial barrier into the extracortical glial
layer. These findings represent the initial stage of cortical dysplasia [Nakano et al., 1996; Yamamoto et al.,
1996, 1997]. The pathological change was milder at
earlier gestational ages.
The eventual outcomes confirmed the prenatal predictions of FCMD to be correct in the three families
who elected to terminate the pregnancies. We antici-
Fig. 4. a: Macroscopic appearance of the Family E fetal brain at 17
gestational weeks. Arrowheads indicate small granular protrusions which
were a characteristic feature of the FCMD fetal brain. These were smaller
and much less numerous than on the brains from the Family B and Family
C fetuses. b: Microscopically, the linear structure showed irregular disruption. The pathological change was milder, presumably due to the earlier
gestational age (PAM ×400).
316
Saito et al.
pate a growing demand for this service. We are moving
ahead slowly, considering the many ethical issues inherent to prenatal diagnosis. We would like to emphasize that Families A, D, F, G, and H would most likely
have opted for abortion without the assurance, provided by prenatal diagnosis, that their babies would be
healthy. Family E also represents a special case in that
having three afflicted children would be an enormous
burden on one family. Ultimately, the decision as to
whether to utilize prenatal diagnosis, and if it is utilized, what to do with the information obtained, must
be made by the parents. Our job, as physicians, is to
support these families both medically and educationally.
Kondo E, Saito K, Toda T, Osawa M, Yamamoto T, Kobayashi M, Fukuyama Y (1996): Prenatal diagnosis of Fukuyama type congenital muscular dystrophy by polymorphism analysis. Am J Med Genet 66:169–
174.
ACKNOWLEDGMENTS
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We thank the family members who participated in
this study. We also thank Drs. Tadayuki Ishihara, Hiroshi Nakai, Setsuko Tsuchiya, Hitoshi Kosaka, Yuzo
Tanabe, Shin Nagata, and Sumimasa Yamashita for
introducing the patients, and Dr. Bierta Barfod for
reading the manuscript. This work was supported by
a research grant for Nervous and Mental Disorders
(8A-2, 8A-3) from the Ministry of Health and Welfare of
Japan, and also by a Grant- in-Aid for Scientific Research (07670906) from the Ministry of Education, Science, and Culture, Japan.
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markers, using, prenatal, eighth, typed, congenital, new, familie, dystrophy, japanese, fukuyama, haplotype, analysis, genes, closest, muscular, diagnosis
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