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PubMed1994

Genetic epidemiologic study of hearing loss in an adult population.

Previous population studies of hearing loss have been limited to children with moderate to profound impairment, and have reported that heritability accounts for at least 50% of congenital or early-onset cases. The present study was designed to assess genetic factors associated with late-onset hearing impairment in an adult population. A brief family history and audiologic questionnaire was sent to approximately 11,200 members of the consumer organization, Self Help for the Hard of Hearing, Inc., and 4,039 questionnaires were returned. All respondents reported having at least one previous audiologic exam. Reported data were verified against audiograms when available. Regardless of the reported causes, 49% of early-onset cases (< or = 20 years of age) had one or two parent(s) with some form of hearing loss compared with 62% in later-onset cases. As expected, mean age at onset was substantially younger for cases with positive family histories than cases with negative family histories. Results from nuclear segregation analysis showed that fully recessive and dominant models failed to explain the early- or late-onset hearing loss data. In this nationwide survey, the large proportion of cases with positive family histories clearly indicates the importance of genetic factors in adult-onset forms of hearing loss. Comparison with younger-onset cases will permit further delineation of differences in inheritance patterns. This study should identify more homogeneous groups of adult-onset families for further genetic study, and provide empiric information for use in genetic counselling.

Adult↗
PubMed1995

Genetic study of nonsyndromic coronal craniosynostosis.

From a series of 1265 individuals with different craniosynostoses hospitalized between 1976 and 1993, 260 probands with nonsyndromic unilateral (181) or bilateral (79) coronal synostosis were analysed. The prevalence of craniosynostoses was estimated as 1 in 2100 children. In the group of coronal synostosis, family history was obtained on 192 probands in 180 pedigrees. The male:female ratio was 1:2. The average paternal age was 32.7 +/- 6.4 years, which is significantly higher than normal. In 26 of the 180 pedigrees, a high degree of familial aggregation was observed, giving a 14.4% figure of familial cases. The bicoronal synostoses were significantly more often familial than the unicoronal synostoses. Segregation analysis of these families leads to the conclusion that coronal synostosis is transmitted as a dominant disorder with 0.60 penetrance and 61% of sporadic cases.

Adult↗
PubMed1995

Absence of linkage of apparently single gene mediated ADHD with the human syntenic region of the mouse mutant Coloboma.

Attention deficit disorder (ADHD) is a complex biobehavioral phenotype which affects up to 8% of the general population and often impairs social, academic, and job performance. Its origins are heterogeneous, but a significant genetic component is suggested by family and twin studies. The murine strain, coloboma, displays a spontaneously hyperactive phenotype that is responsive to dextroamphetamine and has been proposed as a genetic model for ADHD. Coloboma is a semi-dominant mutation that is caused by a hemizygous deletion of the SNAP-25 and other genes on mouse chromosome 2q. To test the possibility that the human homolog of the mouse coloboma gene(s) could be responsible for ADHD, we have carried out linkage studies with polymorphic markers in the region syntenic to coloboma (20p11-p12). Five families in which the pattern of inheritance of ADHD appears to be autosomal dominant were studied. Segregation analysis of the traits studied suggested that the best fitting model was a sex-influenced, single gene, Mendelian pattern. Several genetic models were evaluated based on estimates of penetrance, phenocopy rate, and allele frequency derived from our patient population and those of other investigators. No significant linkage was detected between the disease locus and markers spanning this chromosome 20 interval.

Adolescent↗
PubMed2003

X-inactivation pattern in multiple tissues from two Leber's hereditary optic neuropathy (LHON) patients.

The more frequent manifestation of ophthalmological abnormalities in males, relative to females, is an unexplained feature of Leber's hereditary optic neuropathy (LHON) that suggests an X-linked modifying gene acting in concert with the pathogenic LHON mitochondrial DNA (mtDNA) mutation. In addition, segregation analysis of the optic neuropathy in LHON pedigrees was compatible with the presence of a recessive-modifying gene on chromosome X. According to this two-locus model, females would be affected only if homozygous or if they were susceptible to skewed X-inactivation. Attempts both to localize the putative LHON-modifying gene by linkage analysis and to find an excess of skewed X-inactivation in affected females were unsuccessful, although the inactivation pattern was only studied in DNA isolated from blood cells. We had the opportunity to analyze a wide range of tissues at autopsy, including the optic nerves and the retina, from two LHON female patients. We found no evidence of skewed X-inactivation in the affected tissues, thus weakening further the hypothesized involvement of a specific X chromosome locus in the pathophysiological expression of LHON.

Adult↗
PubMed2004

A patient with Prader-Willi syndrome and a supernumerary marker chromosome r(15)(q11.1-13p11.1)pat and maternal heterodisomy.

We report on a Prader-Willi patient with a de novo supernumerary marker chromosome (SMC) in 16% of the cells. The SMC was a ring chromosome and it included the PWS/AS critical region as was demonstrated by FISH. Segregation analysis indicated that the SMC originated from a paternal chromosome 15 and the two normal chromosomes 15 of the patients were of the maternal homologues. Namely, the patient had maternal heterodisomy in 85% of the cells and triplication of the PWS/AS region in 15% of the cells. The Prader-Willi features were the result of the low mosaicism of the SMC. The evolution of the maternal heterodisomy and the SMC were two unrelated events, the occurrence of both events in the same embryo rescued it from lethality.

Blotting, Southern↗
PubMed2005

Inheritance pattern of Beckwith-Wiedemann syndrome is heterogeneous in 291 families with an affected proband.

Beckwith-Wiedemann syndrome (BWS) is congenital disorder whose molecular etiology is related to genetic and epigenetic mutations on 11p15. The majority of cases of BWS are sporadic, but a substantial proportion are familial, with an unknown inheritance pattern, although autosomal dominant and sex-dependent inheritance have been proposed. We tested the hypothesis that in familial BWS, autosomal dominant inheritance is the primary mode of transmission underlying familial instances. Segregation analysis was performed in 291 families ascertained with an affected child. Individuals were considered to have BWS if they had two of five major features: macroglossia, macrosomia, hypoglycemia at birth, abdominal wall defect, and ear pits or creases. Models of inheritance were tested using pedigree analysis package (PAP) parameterized for a discrete trait. A total of 291 families of an affected proband were included in the study. The analysis was based on a revised general model that included a boundary solution. Sporadic and environmental models were rejected. Overall, the results suggested Mendelian inheritance but under recessive or additive mode of inheritance, which fit the data equally well rather than dominant inheritance. However, the presence of families in the cohort consistent with dominant and sex-dependent inheritance suggest familial BWS may be a heterogeneous group comprised of different inheritance patterns. Familial BWS does not appear to be consistent with autosomal dominant transmission, and is likely a complex mixture of different inheritance patterns.

Beckwith-Wiedemann Syndrome↗
PubMed2005

Three cases with de novo 6q imbalance and variable prenatal phenotype.

We describe two families in which three fetuses had a de novo 6q imbalance and abnormal phenotypes. We determined the boundaries and the parental origin of the chromosomal alterations by segregation analysis using a panel of short tandem repeats (STRs) located on 6q. Cases 1 and 2 (family A) were two sibs with 6q imbalance involving different regions. Case 1 was a female fetus with arthrogryposis, who had a complex rearrangement resulting in two deleted regions (6q22 and 6q25.1-q25.2) and a duplication of 6q23-q25.1. This latter imbalance was reported previously and is associated with joint contractures and short neck, also present in this fetus. The sib (case 2) had intrauterine growth restriction (IUGR) and agenesis of the ductus venosus. This male died shortly after birth; postnatal karyotype and molecular investigations showed a 6q21 de novo deletion. Case 3 (family B) had a prenatally detected deletion of 6q14-q16. Autopsy of the fetus documented minor facial anomalies and contractures of the limbs. All rearrangements were de novo and of paternal origin. Our data and the consistent number of cases of de novo 6q alterations previously reported suggest that chromosome arm 6q could be prone to rearrangements resulting in heterogeneous phenotypes. In family A, chromosome 6q imbalances involving different chromosomal regions were present in two consecutive pregnancies. In such cases counseling should suggest the impossibility of excluding recurrence of a chromosomal imbalance, and should discuss the option of early prenatal diagnosis in subsequent pregnancies.

Chromosome Aberrations↗
PubMed2004

Linkage of eye movement dysfunction to chromosome 6p in schizophrenia: additional evidence.

Establishing the genetics of physiological traits associated with schizophrenia may be an important first step in building a neurobiological bridge between the disease phenotype and its genetic underpinnings. One of the best known of the traits associated with schizophrenia is a disorder of smooth pursuit eye tracking (ETD), which is present in 50-80% of schizophrenia patients. ETD is more than three times more prevalent in the families of a schizophrenia patient than is schizophrenia itself. Arolt et al. [1999] estimated LOD scores for ETD of 2.85 for D6S282 and 3.70 for D6S271, two markers on 6p21.1, as well as obtaining an indication of possible linkage for schizophrenia. Our sample comprised two large families in Denmark. Markers in the region that was implicated by the study of Arolt et al. [1996, 1999] were analyzed as part of a genome scan using the "latent trait (L.T.) model" for the co-transmission of schizophrenia and ETD that we had previously fitted to segregation analysis data from Norway. We obtained a LOD score of 2.05 for D6S1017, a marker within 3 cM of the positive markers obtained by Arolt et al. [1996, 1999]. We regard our results as independent evidence supporting the findings of Arolt et al. [1996, 1999] and also as support for the L.T. model as a way of combining the traits ETD and schizophrenia.

Case-Control Studies↗
PubMed1978

The genetic hypothesis for the transmission of Australia antigen (HBsAg).

Exceptions have been cited which rule against the simple autosomal recessive hypothesis for the transmission of susceptibility to infection with Australia antigen (HBsAg). An attempt is made here to present a genetic model for a complex segregation analysis of a new and unique set of data to test this hypothesis. Regression techniques were used to estimate in four populations, age and sex-specific penetrance levels and the frequency of the gene whose product is hypothesized to be HBsAg. While the genetic hypothesis was not in general supported, observed deviations and their possible causes are discussed.

Adolescent↗
PubMed1983

Genetic and evolutionary implications in peptic ulcer disease.

The evidence for a genetic component in peptic ulcer disease has been based on twin, family, and blood group studies. A polygenic model for the inheritance of peptic ulcers has been displaced by a genetic heterogeneity model based on several lines of evidence, some of the most powerful being recent work using subclinical markers. One marker in particular, an elevated level of serum pepsinogen I (PG I), a pepsin precursor produced by the gastric mucosa, secreted into the stomach lumen and also appearing in the bloodstream, has been found to be associated with a subgroup of duodenal ulcer patients. Segregation analysis of elevated serum PG I in duodenal ulcer sibships demonstrates familial aggregation consistent with autosomal dominant inheritance. Elevated PG I is also accompanied by gastric hyperacidity and presumably indicates those individuals with an increased mass of chief and parietal cells, and thus an increased capacity for peptic activity, an important element in the pathogenesis of ulcer disease. An evolutionary hypothesis based on selection for peptic activity and acidity is offered to explain several of the epidemiologic and genetic elements of this group of chronic diseases.

Biological Evolution↗
PubMed1985

A family study of dermatoglyphic traits in India: a search for major gene effects on palmar pattern ridge counts.

Palmar pattern ridge counts were subjected to segregation analysis in an attempt to identify possible major gene effects on these dermatoglyphic traits. The phenotypes considered were total palmar pattern ridge count, and ridge counts for the right interdigital III and IV and left interdigital IV individual palmar areas (sample sizes were too small for the other palmar areas). Evidence of familial resemblance was found for all of the phenotypes studied, and initial evidence for a major effect was found for all but the right palm interdigital III ridge count. However, this initial evidence could be attributed to nongenetic effects in each case, including skewness in the trait distribution. Tests for agreement with Mendelian transmission frequencies were found to be very useful in discriminating between a non-Mendelian major effect and a major gene. We concluded against a major gene effect for any of these traits, and multifactorial inheritance remains a plausible alternative explanation for the familial resemblance.

Dermatoglyphics↗
PubMed2005

Confirmation of a hereditary motor and sensory neuropathy IIC locus at chromosome 12q23-q24.

Hereditary motor and sensory neuropathy type IIC (HMSN IIC) is an autosomal dominant axonal neuropathy. The cardinal features include distal muscle wasting and weakness, vocal cord paralysis, and mild sensory impairment. Recently, HMSN IIC locus was mapped to chromosome 12q23-24. Two families affected by HMSN IIC were identified and evaluated for linkage to this region. Segregation analysis in both families was consistent with linkage to chromosome 12q23-24. Combined analysis generated a multipoint LOD score of 2.1 at marker D12S1583 and refined the HMSN IIC gene interval to The clinical and molecular findings are discussed.

Adolescent↗
PubMed1997

A proposed mutation, Val781Ile, associated with hyperkalemic periodic paralysis and cardiac dysrhythmia is a benign polymorphism.

Twenty different point mutations have been identified in the gene coding for the alpha subunit of the adult skeletal muscle sodium channel in families with hyperkalemic periodic paralysis, paramyotonia congenita, and the potassium-aggravated myotonias. One novel mutation (Val(781)Ile) was reported in an adopted boy with potassium-sensitive weakness and cardiac dysrhythmia. The confidence in establishing this rare amino acid substitution as a causative mutation was limited by the absence of family members for segregation analysis. Functional expression studies herein show that Val(781)Ile is most likely a benign polymorphism and not a disease-associated mutation.

Adult↗
PubMed1993

HLA-linked susceptibility to rheumatoid arthritis. A study of forty-one multicase families from northern India.

OBJECTIVE: To analyze segregation of rheumatoid arthritis (RA) with HLA-DR4 and/or other alleles in multicase RA families and to compare the segregation patterns among affected and unaffected sibs. METHODS: Forty-one multicase families (22 multiplex and 19 simplex) of northern Indian origin were studied for HLA haplotype segregation. RESULTS: HLA haplotype sharing among affected sibs was observed more often than expected in families in which both parents were healthy (P < 0.05). RA cosegregated with a DR4 haplotype among offspring only in multiplex families in which both parents were unaffected (P < 0.05), while in simplex families, the disease segregated with DR4 only when the allele was from the affected DR4-heterozygous parent. In DR4-negative affected sib pairs, DR1, DR6, and DR10 were inherited from healthy parents more often than expected. CONCLUSION: Dissimilar modes of inheritance are seen among multiplex and simplex RA families. The results of segregation analysis are compatible with the hypothesis that an epitope, rather than an individual DR antigen(s), is responsible for increased risk for development of RA.

Adolescent↗
PubMed1982

T cell idiotypes recognizing self-major histocompatibility complex molecules: H-2 specificity, allotype linkage, and expression on functional T cell populations.

An anti-idiotypic serum (antiserum 5936, B. Rubin et al., J. Exp. Med. 1979. 150: 307) was used to demonstrate receptor sites for self-major histocompatibility complex (MHC) antigens on T lymphocytes. The antiserum was raised by injecting rabbits tolerant to mouse Ig with a B6 anti-CBA (anti-H2k) alloantibody. It recognized a large proportion of T cells from H-2k strains carrying the b, c, d or e allele at the Igh-1 locus, but only a few T cells from H-2k strains with Igh-1 alleles a, f and j. Allotype linkage of the 5936 idiotype was also demonstrated by segregation analysis. The antiserum did not recognize either H-2k B cells or T cells from other H-2 haplotypes despite the presence of a permissive Igh-1 allele. The 5936 idiotype was found to be associated with several different antigen specificities, indicating that it is not located on the binding site for foreign antigen. Furthermore, the 5936 antiserum inhibited the binding of soluble Ik antigens by H-2k, Igh-1b, T cells, and, in the presence of complement, eliminated T cells responding to different antigens in an I-Ak-restricted fashion. Collectively, the data indicate that the structure bearing the 5936 idiotype is a receptor for I-Ak antigens, expressed by strains carrying the I-Ak allele and a permissive allele at the Igh-1 locus. The relevance of this finding to the MHC-restricted recognition of antigens by T cells is discussed.

Animals↗
PubMed1987

Identification of interleukin 2-producing T helper cells within murine Lyt-2+ T lymphocytes: frequency, specificity and clonal segregation from Lyt-2+ precursors of cytotoxic T lymphocytes.

The prime aim of this study was to assess whether the autonomous primary mixed lymphocyte culture response of Lyt-2+ T cells towards class I major histocompatibility complex (MHC) antigens reflects in terms of interleukin 2 (IL2) production and cytotoxicity the activation of multifunctional Lyt-2+ T cells, or the activation of functionally distinct T cell subsets. The results demonstrate that highly purified Lyt-2+ T cells proliferate in response to class I MHC antigens, as opposed to L3T4+ T cells which react towards class II MHC antigens. In both responder cell types proliferative responses are associated with IL2 secretion, while only Lyt-2+ T cells develop measurable cytotoxic effector cells. The precursor frequency of IL2-producing helper cells in MHC class I-reactive Lyt-2+ T cells equals that in MHC class II-reactive L3T4+ T cells (f = 1/500-1/1000). In clonal segregation analysis greater than 90% of Lyt-2+ colonies secreting IL2 do not develop cytotoxic activity, while greater than 90% of Lyt-2+ cytotoxic T cells fail to produce detectable IL2. A minority of less than 10% of Lyt-2+ T cells appears to be bifunctional. As such the results point out the existence of functionally committed T cells within class I MHC-reactive Lyt-2+ T cells able to produce either IL2 or to develop into cytotoxic effector cells.

Animals↗
PubMed1997

Conservation of a master hematopoietic switch gene during vertebrate evolution: isolation and characterization of Ikaros from teleost and amphibian species.

The generation of T, B and NK lymphocyte lineages from pluripotent hematopoietic stem cells is dependent upon the early expression of the Ikaros locus which by means of alternative splicing produces a variety of zinc finger DNA binding transcription factors. We assessed the general biological importance of Ikaros by studying its conservation and expression in teleost fish and amphibians. Portions of Ikaros cDNA from rainbow trout and Xenopus were amplified by reverse transcription-polymerase chain reaction (RT-PCR). They show roughly 75% conservation of the amino acid sequence with mammalian Ikaros. The trout fragment was then used to isolate full-length Ikaros clones from a trout thymocyte cDNA library. In mice and humans, Ikaros produces six alternatively spliced isoforms, but in trout two additional novel splice variants designated Ik-7 and Ik-8 were also found. Ik-7 is expressed in a similar fashion to Ik-1 and Ik-2, the predominant isoforms expressed in mammalian lymphocytes. In trout and zebrafish, as in mammals, Ikaros is a single-copy gene, but in Xenopus segregation analysis demonstrates that Ikaros has been duplicated, most likely a result of polyploidization. We then examined the expression of Ikaros in trout and Xenopus tumor T cell lines via Northern blot, RT-PCR, immunofluorescence and Western blot analysis. Overall, Ikaros is expressed in a lymphoid-specific fashion similar to that found in mice and humans. In addition Ikaros is expressed early in trout ontogeny, beginning roughly at days 3-4 in the yolk sac and at day 5-6 in the embryo proper. The conservation of Ikaros structure and expression confirms it as a master switch of hematopoiesis.

Alternative Splicing↗
PubMed1990

Hereditary subtypic patterns detected in the Ba fragment of complement factor B: occurrence of four common alleles in Japanese.

A procedure which can detect subtype-specific minor bands of factor B (BF) by polyacrylamide gel isoelectric focusing is presented. After zymosan-mediated fragmentation of BF in serum via alternative pathway for complement activation, serum samples are subjected to isoelectric focusing in a narrow pH range (4.2-4.9). The Ba fragments are detected by using immunoblotting. In addition to the previously reported minor bands with subtypic specificities, heterogeneities are observed in other minor band group, where a single minor band corresponds exclusively to a subtype in a regular combination with the previously announced subtypic patterns. A one-to-one correspondence of a single band to each subtype provides an unambiguous determination for three subtypic phenotypes deduced from the two divided BF*F alleles, BF*FA and BF*FB. An autosomal codominant heredity is confirmed through segregation analysis. A population survey reveals that four common alleles, BF*S, BF*FA, BF*FB, BF*Fb1, occur in a Japanese population and the former three alleles, except BF*Fb1, occur in a Cambodian population. The presence or absence of a single anodal minor band was found to be the only difference after neuraminidase treatment of FA and FB, implying that an amino acid substitution responsible for the FA-FB subtypic difference is involved in an additional acquisition in FA of an oligosaccharide unit with a charged sialic acid.

Alleles↗