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PubMed2001

Biodemographic study of a central Apennine area (Italy) in the 19th and 20th centuries: marriage seasonality and reproductive isolation.

This study investigates seasonality of marriages and reproductive isolation in six long-isolated communities in the central Apennines (Italy). It had two objectives: (1) the identification of an Apennine biodemographic model in comparison with mountain communities of other regions, and with non-Apennine communities in Abruzzo, and (2) to identify the possible effects of the drainage of Lake Fucino (1854-1876) on that area. Marriages in this region show two very stable seasonal patterns: one is typical of sedentary rural societies, with summer migrations and marriages preferentially celebrated in the winter, and the other has marriages that are strongly concentrated in the summer months, i.e. between 75% and 93.5% of marriages were celebrated between June and October in these communities in the 1800s. These were traditionally pastoral communities with winter transhumance of the flocks and their shepherds towards the lowlands of southern Italy. In both groups, restrictions imposed by the Catholic Church do not seem to have affected the timing of marriages. Indeed, economic factors related to work activities seem to have had more influence. Concerning reproductive isolation, the results show high rates of endogamy: between 85% and 98% in both the 19th and 20th centuries. Rates of consanguineous marriages were between 5% and 20%, and those of isonymous marriages rarely exceeded 9%. The coefficient of inbreeding a shows that there was a delayed, limited period of increased consanguinity in the few decades around the turn of the century. This is different from the national situation, and thus could be a consequence of the Lake Fucino drainage.

Altitude↗
PubMed2006

A novel GDAP1 mutation 439delA is associated with autosomal recessive CMT disease.

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is the most common form of inherited motor and sensory neuropathy. Based on neurophysiological and neuropathological criteria CMT has been sub-classified into two main types: demyelinating and axonal. Furthermore, it is genetically heterogeneous with autosomal dominant, autosomal recessive (AR) and X-linked modes of inheritance. Thus far, seven genes have been identified in association with the demyelinating AR-CMT disease. We hereby report our clinical and molecular genetic findings in a consanguineous family with AR-CMT. METHODS: Two young sisters with AR-CMT and other non-affected family members were clinically and electrophysiologically evaluated and then molecular genetic investigation was carried out in order to identify the pathogenic mutation. RESULTS: Following an initial indication for linkage of the family to the CMT4A locus on chromosome 8, we sequenced the Ganglioside-induced differentiation-associated protein 1 (GDAP1) gene and identified a single nucleotide deletion in exon 3 that is associated with AR-CMT in the family. CONCLUSIONS: We identified a novel GDAP1 439delA mutation that is associated with AR-CMT in a consanguineous family of Iranian descent with two affected young girls and a history in other members of the family.

Charcot-Marie-Tooth Disease↗
PubMed2001

Selective recovery of founder genetic diversity in aquacultural broodstocks and captive, endangered fish populations.

Hatchery broodstocks used for genetic conservation or aquaculture may represent their ancestral gene pools rather poorly. This is especially likely when the fish that found a broodstock are close relatives of each other. We re-analysed microsatellite data from a breeding experiment on red sea bream to demonstrate how lost genetic variation might be recovered when gene frequencies have been distorted by consanguineous founders in a hatchery. A minimal-kinship criterion based on a relatedness estimator was used to select subsets of breeders which represented the maximum number of founder lineages (i.e., carried the fewest identical copies of ancestral genes). UPGMA clustering of Nei's genetic distances grouped these selected subsets with the parental gene pool, rather than with the entire, highly 'drifted' offspring generation. The selected subsets also captured much of the expected heterozygosity and allelic diversity of the parental gene pool. Independent pedigree data on the same fish showed that the selected subsets had more contributing parents and more founder equivalents than random subsets of the same size. The estimated mean coancestry was lower in the selected subsets, meaning that inbreeding in subsequent generations would be lower if they were used as breeders. The procedure appears suitable for reducing the genetic distortion due to consanguineous and over-represented founders of a hatchery gene pool.

Alleles↗
PubMed1973

The genetic origin of leucocytic mucopolysaccharides in cancer patients.

The presence or absence of lymphocytic mucopolysaccharides (MPS) is studied in 223 subjects: 100 normals (controls); 8 cancer patients cured for more than 6 years; 30 cancer patients at the start of their treatment; and 85 relatives of first degree consanguinity of these last patients. The data are studied by statistical and genetic analysis. The results confirm the findings reported earlier and show that the difference in the probability of a high frequency of leucocytic MPS between the relatives of cancer patients and the controls is highly significant. Furthermore, this probability in a relative of first degree of consanguinity of a cancer patient is more than three times greater than in an individual of the general population. Genetic segregation analysis shows that the high leucocytic MPS trait segregates in the families of cancer patients after a classic pattern of dominant autosomal inheritance. Applying Falconer's nomogram it is concluded that the whole of this phenotypic variation is of genetic origin. Its interrelationships with cancer are discussed and it is postulated that this disturbance of the lymphocytic MPS represents a subclinical variant, not known until now, of the clinical mucopolysaccaridoses.

Chromosome Aberrations↗
PubMed1995

Hind III genomic polymorphism of the C3b receptor (CR1) in patients with SLE: low erythrocyte CR1 expression is an acquired phenomenon.

Expression of the human erythrocyte C3b receptor (CR1-CD35) and its Hind III RFLP was studied in a group of 37 patients with SLE, 15 consanguineous relatives of the patients and 48 healthy normal subjects. The CR1 number on erythrocytes was quantitated by ELISA using a mAb to CR1. Serum levels of complement proteins (C3, C4, C3d) and circulating immune complexes (CIC) were estimated simultaneously in controls and relatives. The patients were followed up during the course of the treatment. The CR1/erythrocyte (CR1/E) in patients were found to be significantly low in comparison to controls. The gene frequencies for the alleles H and L (7.4 and 6.9 kb Hind III restriction fragments) in the patients were 0.75 and 0.25, respectively, which did not differ significantly from the controls (0.77 and 0.23 in normal subjects and 0.79 and 0.21 in consanguineous relatives of the patients). However, patients expressed fewer CR1/E within each genotype than their relatives and healthy subjects. CR/E was found to be stable in consecutive samples in controls. In patients, the numbers varied between low and high during the course of the treatment. The variation in the numbers was significantly correlated with C3d and CIC as well as with the severity of the disease. Our results suggest that low levels of CR1 on erythrocytes in SLE patients are required during the course of the disease and that the 6.9 kb restriction fragment does not play a role in causing susceptibility to the disease.

Adolescent↗
PubMed2000

A gene for ataxic cerebral palsy maps to chromosome 9p12-q12.

Cerebral palsy (CP) has an incidence of approximately 1 in 750 births, although this varies between ethnic groups. Genetic forms of the disease account for about 2% of cases in most countries, but contribute a larger proportion in certain sub-types of the condition and in populations with a large proportion of consanguineous marriages. Ataxic cerebral palsy accounts for 5-10% of all forms of CP and it is estimated that approximately 50% of ataxic cerebral palsy is inherited as an autosomal recessive trait. We have identified a complex consanguineous Asian pedigree with four children in two sibships affected with ataxic cerebral palsy and have used homozygosity mapping to map the disorder in this family. A genome-wide search was performed using 343 fluorescently labelled polymorphic markers and linkage to chromosome 9p12-q12 was demonstrated. A maximum Lod score of 3.4 was observed between the markers D9S50 and D9S167 using multipoint analysis, a region of approximately 23cM. We have identified a family that segregates both ataxic CP and ataxic diplegia and have mapped the genetic locus responsible in this family to chromosome 9p12-q12. The identification of gene(s) involved in the aetiology of CP will offer the possibility of prenatal/premarital testing to some families with children affected with the disorder and will greatly increase our understanding of the development of the control of motor function.

Alleles↗
PubMed2002

Identification of a locus on chromosome 2q11 at which recessive amelogenesis imperfecta and cone-rod dystrophy cosegregate.

A consanguineous Arab pedigree in which recessive amelogenesis imperfecta (AI) and cone-rod dystrophy cosegregate, was screened for linkage to known retinal dystrophy and tooth abnormality loci by genotyping neighbouring microsatellite markers. This analysis resulted in linkage with a maximum lod score of 7.03 to the marker D2S2187 at the achromatopsia locus on chromosome 2q11, and haplotype analysis placed the gene(s) involved in a 2 cM/5 Mb interval between markers D2S2209 and D2S373. The CNGA3 gene, known to be involved in achromatopsia, lies in this interval but thorough analysis of its coding sequence revealed no mutation. Furthermore, affected individuals in four consanguineous recessive pedigrees with AI but without CRD were heterozygous at this locus, excluding it as a common cause of non-syndromic recessive AI. It remains to be established whether this pedigree is segregating two closely linked mutations causing disparate phenotypes or whether a single defect is causing pathology in both teeth and eyes.

Amelogenesis Imperfecta↗
PubMed2003

Homozygosity mapping of Marinesco-Sjögren syndrome to 5q31.

Marinesco-Sjögren syndrome (MSS), first described in 1931, is an autosomal recessive condition characterised by somatic and mental retardation, congenital cataracts and cerebellar ataxia. Progressive myopathy was later reported to be also a cardinal sign of MSS, with myopathic changes on muscle biopsies. Hypergonadotrophic hypogonadism and skeletal deformities related to pronounced hypotonia were also reported. The major differential diagnosis of MSS is the syndrome defined by congenital cataracts, facial dysmorphism and peripheral neuropathy (CCFDN), which is localised to 18qter. Using homozygosity mapping strategy in two large consanguineous families of Turkish and Norwegian origin, respectively, we have identified the MSS locus on chromosome 5q31. LOD score calculation, including the consanguinity loops, gave a maximum value of 2.9 and 5.6 at theta=0 for the Turkish and the Norwegian families, respectively, indicating linkage between the disease and the D5S1995-D5S436 haplotype spanning a 9.3 cM interval. Patients of the two families presented with the strict clinical features of MSS. On the other hand, the study of two smaller French and Italian families, initially diagnosed as presenting an atypical MS syndrome, clearly excluded linkage from both the MSS locus on 5q31 and the CCFDN locus in 18qter. Patients of the two excluded families had all MSS features (but the myopathic changes) plus peripheral neuropathy and optic atrophy, and various combinations of microcornea, hearing impairment, seizures, Type I diabetes, cerebral atrophy and leucoencephalopathy, indicating that only the pure MSS syndrome is a homogeneous genetic entity.

Cataract↗
PubMed2003

Compound heterozygosity for mutations in the hairless gene causes atrichia with papular lesions.

BACKGROUND: Congenital atrichias represent a complex and heterogeneous group of genodermatoses, which have been shown in several consanguineous families to result from homozygous mutations in the hairless gene (HR). OBJECTIVES: To identify the molecular basis of congenital atrichia in a non-consanguineous family. METHODS: Genetic analysis was carried out in a two-generation family with two children with congenital atrichia and one healthy child. RESULTS: We established a diagnosis of atrichia with papular lesions based on clinical and histopathological data. We identified a heterozygous 11-bp deletion (189-199del) in the two affected children and their mother. In addition, the two affected children and their father were shown to carry a non sense mutation (Q478X), which has previously been described in a Pakistani family. Haplotype analysis revealed that mutation Q478X occurred independently in the two families. CONCLUSIONS: We have identified the first case of compound heterozygosity for mutations in HR as well as the first instance of a recurrent mutation in this gene. These data further expand our understanding of the molecular pathomechanisms underlying congenital atrichias.

Alopecia↗
PubMed2003

Molecular analysis of 5alpha-reductase type 2 gene in eight unrelated egyptian children with suspected 5alpha-reductase deficiency: prevalence of the G34R mutation.

OBJECTIVE: Analysis of the 5alpha-reductase type 2 (SRD5A2) gene in Egyptian patients with suspected 5alpha-reductase (5alphaR) deficiency. PATIENTS AND METHODS: Eight unrelated patients, originating from different geographical areas of Egypt, were referred to the Department of Pediatrics. Six prepubertal and two postpubertal patients presented with ambiguous genitalia. Four were being reared as females while the others were being reared as males. Six patients were products of consanguineous marriages. All patients had 46,XY karyotype. Basal and post-human chorionic gonadotrophin (hCG) stimulation plasma levels of testosterone and dihydrotestosterone were determined. Sequencing of five exons of the SRD5A2 gene was carried out. RESULTS: All patients had normal male testosterone levels, both basal and post-hCG stimulation. The T/DHT ratio was available for six patients and showed values that ranged from normal to high. Three different homozygous mutations were identified. One patient carried a Y235F substitution and two had a N160D substitution. Interestingly, all five of the other patients had the G34R mutation. The parents were heterozygous for the mutations, although the mother of one patient was homozygous for the G34R mutation. CONCLUSION: Among eight unrelated Egyptian children with 5alpha-reductase deficiency, the G34R mutation was identified in five patients. The high consanguinity rate in Egypt suggests a common ancestor with a founder gene effect in cases of G34R mutation.

Adolescent↗
PubMed1975

Lymphocytotoxic antibody in inflammatory bowel disease. A family study.

The prevalence of lymphocytotoxic antibody in inflammatory bowel disease is 40 per cent. Twenty-seven of 90 relatives of 23 probands with the disease (30 per cent) demonstrated lymphocytotoxic antibody, as contrasted with only three of 69 control family members (4 per cent) (P less than 0.0001). Decreased lymphocytotoxicity against lymphocytes from patients with inflammatory bowel disease as compared to normal donor lymphocytes previously demonstrated in the serum of probands was also observed in the serums from family members of the probands. Nineteen of the 48 household contacts of probands (40 per cent) were positive for antibody, whereas eight of 42 nonhousehold contacts (19 per cent) demonstrated it (P less than 0.05). Eight of 16 spouses (50 per cent) of probands showed antibody. The increased prevalence of lymphocytotoxic antibody in family members of probands and its occurrence mainly in household contacts (consanguineous and non-consanguineous) may indicate the exposure of probands and their family members to a common environmental agent.

Adult↗
PubMed1999

Exclusion of AR-CHED from the chromosome 20 region containing the PPMD and AD-CHED loci.

Congenital hereditary endothelial dystrophy (CHED) is a disorder of the corneal endothelium and has been recognized to segregate in families with both autosomal dominant (AD) and autosomal recessive (AR) modes of transmission. AD-CHED has been previously linked to the pericentric region of chromosome 20. Posterior polymorphous dystrophy (PPMD), a corneal endothelial disorder showing phenotypic overlap with CHED, has also been previously genetically mapped to this region. The genetic interval containing AD-CHED is within the larger genetic interval containing the PPMD locus. This study sought to determine whether AR-CHED segregating in a consanguineous Saudi Arabian pedigree is linked to the previously mapped and overlapping loci for AD-CHED and PPMD on the pericentric region of chromosome 20. Forty members of a consanguineous Saudi Arabian pedigree segregating AR-CHED were ascertained. Short tandem-repeat polymorphic markers from the 20 cM interval on chromosome 20 containing both the PPMD and AD-CHED loci were used to genotype these individuals. LOD score analysis of the genotype data with the MENDEL software package utilizing a model of autosomal recessive inheritance with complete penetrance showed exclusion of CHED from the entire PPMD/AD-CHED interval by utilizing overlapping intervals of LOD scores of at least -2. The results obtained demonstrate that AR-CHED is not allelic to either AD-CHED or PPMD, although it has been proposed that AD-CHED may be allelic to PPMD. Thus, there are at least two genes responsible for CHED and PPMD.

Chromosome Mapping↗
PubMed1982

Evidence for the horizontal acquisition of murine AKR virogenes by recent horizontal infection of the germ line.

Several recent reports (8, 10, 11, 13) have established the biological and molecular genetic similarity between the endogenous AKV virus of strain AKR, and an N-ecotropic endogenous virus found in the genome of feral Japanese mice, Mus musculus molossinus. The similarities are so striking as to suggest a common origin of these viruses, which are present in some, but not all, inbred mouse strains. The virogenes of AKR mice may have been acquired by either: (a) common descent of AKR (and other AKV(+) strains) from a common ancestor of AKR and molossinus animals, or (b) horizontal germ line infection of the AKR strains by molossinus virus at 1;he strain's inception followed by fixation through inbreeding. The sexual descent model carries with it a prediction of relative consanguinity of the AKR strain and molossinus, whereas the horizontal infection model does not. We have examined the polymorphic allozyme (allelic isozyme) genotype of 51 nonvirus-related loci in 17 strains of mice including AKR, C58, BALB/c, Swiss, and molossinus. By comparing the composite allozyme genotype of different inbred and outbred mouse strains, the "genetic distance" statistic was derived. Genetic distance measures the degree of allelic substitution between populations and increases proportionately with the amount of time the populations have been reproductively isolated. The genetic distance computed between molossinus and AKR is large, nearly 5-10 times the distance between known related populations and strains (e.g., C57L vs. C57BL/6). Molossinus had a similarly large distance from AKV negative strains (Swiss, C57L) as it did from AKV- positive strains. Cellular DNA sequences that flank the integrated AKV provirus were analyzed by restriction enzyme digestion of liver DNA from molossinus, AKR, and additional inbred strains that express ecotropic murine leukemia virus. The integration flanks of three AKR provirus sequences, Akv-1, Akv-2, and a third uncharacterized sequence, were not evident in molossinus cell DNA, which contained at least six different proviral integration fragments. These data effectively exclude the interpretation of consanguinity of AKR and molossinus and support the notion of acquisition of the endogenous virus in AKR by horizontal infection of the molossinus virus.

AKR murine leukemia virus↗
PubMed1998

Identification of a new locus for a peculiar form of congenital muscular dystrophy with early rigidity of the spine, on chromosome 1p35-36.

Classical congenital muscular dystrophies (CMDs) are autosomal recessive neuromuscular disorders characterized by early onset of hypotonia and weakness, atrophy of limbs and trunk muscles, contractures, and dystrophic changes in the muscle biopsy. So far, only one gene, LAMA2 (6q2), which encodes the laminin alpha2 chain (or merosin), has been identified in these disorders. Mutations in LAMA2 cause CMD with complete or partial merosin deficiency, detectable by immunocytochemistry on muscle biopsies, and account for approximately 50% of CMD cases. In a large consanguineous family (11 siblings) comprising three children affected by CMD without merosin deficiency, we undertook a genomewide search by homozygosity mapping and analyzed 380 microsatellite markers. The affected children were homozygous for several markers on chromosome 1p35-36. We identified two additional consanguineous families with affected children who also showed linkage to this locus. A maximum cumulative LOD score of 4.48, at a recombination fraction of .00, was obtained with D1S2885. A consistent feature in these three families was the presence of early rigidity of the spine, scoliosis, and reduced vital capacity, as found in rigid-spine syndrome (RSS). This study is the first description of a locus for a merosin-positive CMD and will help to better define the nosology of RSS.

Adolescent↗
PubMed2002

Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome.

Walker-Warburg syndrome (WWS) is an autosomal recessive developmental disorder characterized by congenital muscular dystrophy and complex brain and eye abnormalities. A similar combination of symptoms is presented by two other human diseases, muscle-eye-brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD). Although the genes underlying FCMD (Fukutin) and MEB (POMGnT1) have been cloned, loci for WWS have remained elusive. The protein products of POMGnT1 and Fukutin have both been implicated in protein glycosylation. To unravel the genetic basis of WWS, we first performed a genomewide linkage analysis in 10 consanguineous families with WWS. The results indicated the existence of at least three WWS loci. Subsequently, we adopted a candidate-gene approach in combination with homozygosity mapping in 15 consanguineous families with WWS. Candidate genes were selected on the basis of the role of the FCMD and MEB genes. Since POMGnT1 encodes an O-mannoside N-acetylglucosaminyltransferase, we analyzed the possible implication of O-mannosyl glycan synthesis in WWS. Analysis of the locus for O-mannosyltransferase 1 (POMT1) revealed homozygosity in 5 of 15 families. Sequencing of the POMT1 gene revealed mutations in 6 of the 30 unrelated patients with WWS. Of the five mutations identified, two are nonsense mutations, two are frameshift mutations, and one is a missense mutation. Immunohistochemical analysis of muscle from patients with POMT1 mutations corroborated the O-mannosylation defect, as judged by the absence of glycosylation of alpha-dystroglycan. The implication of O-mannosylation in MEB and WWS suggests new lines of study in understanding the molecular basis of neuronal migration.

Abnormalities, Multiple↗
PubMed2005

SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare disorder of autosomal recessive inheritance that was first described in a large consanguineous Bedouin kindred. HHRH is characterized by the presence of hypophosphatemia secondary to renal phosphate wasting, radiographic and/or histological evidence of rickets, limb deformities, muscle weakness, and bone pain. HHRH is distinct from other forms of hypophosphatemic rickets in that affected individuals present with hypercalciuria due to increased serum 1,25-dihydroxyvitamin D levels and increased intestinal calcium absorption. We performed a genomewide linkage scan combined with homozygosity mapping, using genomic DNA from a large consanguineous Bedouin kindred that included 10 patients who received the diagnosis of HHRH. The disease mapped to a 1.6-Mbp region on chromosome 9q34, which contains SLC34A3, the gene encoding the renal sodium-phosphate cotransporter NaP(i)-IIc. Nucleotide sequence analysis revealed a homozygous single-nucleotide deletion (c.228delC) in this candidate gene in all individuals affected by HHRH. This mutation is predicted to truncate the NaP(i)-IIc protein in the first membrane-spanning domain and thus likely results in a complete loss of function of this protein in individuals homozygous for c.228delC. In addition, compound heterozygous missense and deletion mutations were found in three additional unrelated HHRH kindreds, which supports the conclusion that this disease is caused by SLC34A3 mutations affecting both alleles. Individuals of the investigated kindreds who were heterozygous for a SLC34A3 mutation frequently showed hypercalciuria, often in association with mild hypophosphatemia and/or elevations in 1,25-dihydroxyvitamin D levels. We conclude that NaP(i)-IIc has a key role in the regulation of phosphate homeostasis.

Adolescent↗
PubMed1997

The locus for combined factor V-factor VIII deficiency (F5F8D) maps to 18q21, between D18S849 and D18S1103.

Combined factor V-factor VIII deficiency (F5F8D) is a rare, autosomal recessive coagulation disorder in which the levels of both coagulation factor V and coagulation factor VIII are diminished. In order to map and subsequently clone the gene responsible for this phenotype, DNAs from 19 families (16 from Iran, 2 from Pakistan, and 1 from Algeria) with a total of 32 affected individuals were collected for a genomewide linkage search using genotypes of highly informative DNA polymorphisms. All pedigrees except two contained at least one consanguineous marriage. A maximum LOD score (Zmax) of 14.82 for theta = .02 was generated with marker D18S1129 in 18q21; LOD scores > 9 were obtained for several other markers-D18S849, D18S1103, D18S64, and D18S862. Multipoint analysis resulted in Zmax = 18.91 for the interval between D18S1129 and D18S64. Informative recombinants placed the locus for F5F8D between D18S849 and D18S1103, in an interval of approximately 1 cM. These results are similar to the recently reported linkage of this disease to chromosome 18q in Jewish families (Nichols et al. 1997) and provide evidence that the same gene is responsible for all F5F8D among human populations. The difference in clinical severity of the phenotype in unrelated families, as well as the failure to detect a specific haplotype of DNA polymorphisms in the consanguineous Iranian families, suggests the existence of different molecular defects in the F5F8D gene. There exists an apparently gap-free contig with CEPH YACs linking the two markers on either side of the critical region. Positional cloning efforts are now in progress to clone the F5F8D gene.

Chromosome Mapping↗
PubMed1997

Definitive evidence for an autosomal recessive form of hypohidrotic ectodermal dysplasia clinically indistinguishable from the more common X-linked disorder.

A crucial issue in genetic counseling is the recognition of nonallelic genetic heterogeneity. Hypohidrotic (anhidrotic) ectodermal dysplasia (HED), a genetic disorder characterized by defective development of hair, teeth, and eccrine sweat glands, is usually inherited as an X-linked recessive trait mapped to the X-linked ectodermal dysplasia locus, EDA, at Xq12-q13.1. The existence of an autosomal recessive form of the disorder had been proposed but subsequently had been challenged by the hypothesis that the phenotype of severely affected daughters born to unaffected mothers in these rare families may be due to marked skewing of X inactivation. Five families with possible autosomal recessive HED have been identified, on the basis of the presence of severely affected females and unaffected parents in single sibships and in highly consanguineous families with multiple affected family members. The disorder was excluded from the EDA locus by the lack of its cosegregation with polymorphic markers flanking the EDA locus in three of five families. No mutations of the EDA gene were detected by SSCP analysis in the two families not excluded by haplotype analysis. The appearance of affected males and females in autosomal recessive HED was clinically indistinguishable from that seen in males with X-linked HED. The findings of equally affected males and females in single sibships, as well as the presence of consanguinity, support an autosomal recessive mode of inheritance. The fact that phenotypically identical types of HED can be caused by mutations at both X-linked and autosomal loci is analogous to the situation in the mouse, where indistinguishable phenotypes are produced by mutations at both X-linked (Tabby) and autosomal loci (crinkled and downless).

Adolescent↗