American Caucasian Families Research Articles

A Closer Look at Religiosity Among Family Caregivers

This article addresses the relationships between the dimensions of religiosity and positive appraisal of caregiving among African American, Hispanic, and non-Hispanic Caucasian family caregivers for older adults. Data analysis of 69 subjects revealed a negative correlation between non-organizational religiosity and positive appraisal of care among African American caregivers and a positive correlation between organizational religiosity and positive appraisal of care among Hispanic caregivers. Findings from this analysis challenges the overall assumption that religiosity increases positive appraisal of caregiving. Rather, the nature and outcomes of family caregiving are different for various ethnic groups.

The identification of a new HLA‐DPB1 allele (*1302) in one family and the detection of a recombination event between the DR and the DQ regions in another Caucasian T1DGC family

The analysis of families collected by the T1DGC and typed at high resolution for the HLA class I and class II loci provided an opportunity for identifying new alleles and rare recombination events. In one American Caucasian family, a novel allele (HLA-DPB1*1302), detected as an unusual pattern of probe binding, was identified in the mother and in one child. Amplicons from both individuals were sequenced and a new variant of DPB1*1301 with an A->T mutation [TAC to TTC in codon 64, (amino acid 35); Y to F] was confirmed. In another American Caucasian family, one child inherited an unusual haplotype, DRB1*1501-DQA1*0102-DQB1*0609-DPA1*0103-DPB1*0601 resulting from a recombination between the DRB1 loci on the maternal chromosomes DRB1*1501-DQA1*0102-DQB1*0602-DPA1*0103-DPB1*0401 and DRB1*1302-DQA1*0102-DQB1*0609-DPA1*0103-DPB1*0601.

Mutation analysis of the parkin and PINK1 genes in American Caucasian early-onset Parkinson disease families

Mutations in the parkin gene and the PTEN-induced putative kinase 1 gene (PINK1) have been identified as the most common causes of autosomal recessive early-onset Parkinson disease (EOPD). To investigate the presence of the parkin and PINK1 gene mutation(s) and to explore genotype-phenotype correlations in American Caucasian families with EOPD from North American, we screened these two genes in probands of six families by direct sequencing, semi-quantitative PCR and RT-PCR. No PINK1 gene mutation was found in any of the probands, but compound heterozygous mutations (EX 3 del and EX 3_4 del) in the parkin gene were identified in one family. Extended analysis of the parkin-positive family showed the phenotype of patients was that of classic autosomal recessive EOPD, characterized by early age at onset, slow progression, beneficial response to levodopa, and levodopa-related motor complications. Three heterozygous mutation carriers (EX 3 del or EX 3_4 del) were free of any neurological symptoms. None of 62 healthy controls harbored EX 3 del or EX 3_4 del mutation. Our data suggest that compound heterozygous mutations (EX 3 and EX 3_4 del) in the parkin gene were the cause of EOPD in one of six Caucasian families; heterozygous EX 3 del and heterozygous EX 3_4 del forms were insufficient to cause this disorder, consistent with a loss-of-function mechanism of the parkin mutations. The results may provide new insights into the cause and diagnosis of PD and have implications for genetic counseling.

A novel DRB1*04 allele

Discovery of the novel DRB1*0464 allele is described. This allele contains a nucleotide substitution in codon 13 that changes the amino acid histidine coded for in all other DRB1*04 alleles to tyrosine. This allele was found in a parent and one child of a North American Caucasian family with the haplotype: A*03, B*07, DRB1*0464, DRB4*0103, DQB1*0301.

A novel mutation at the DFNA36 hearing loss locus reveals a critical function and potential genotype–phenotype correlation for amino acid‐572 of TMC1

We ascertained a North American Caucasian family (LMG248) segregating autosomal dominant, non-syndromic, post-lingual, progressive sensorineural hearing loss. The hearing loss begins in the second decade of life and initially affects high frequencies. It progresses to profound deafness at all frequencies by the fourth or fifth decade. The phenotype co-segregates with short-tandem repeat markers flanking the TMC1 gene at the DFNA36 locus on chromosome 9q31-q21. The affected individuals carry a novel missense substitution, p.D572H (c.G1714C), of the TMC1 gene. This mutation is at the same nucleotide and amino acid position as the only other reported DFNA36 mutation, p.D572N (c.G1714A). Our observations implicate a critical function for amino acid-572 for wild-type TMC1 function or the pathogenesis of DFNA36 hearing loss. The slower progression of hearing loss associated with p.D572H, in comparison with that caused by p.D572N, may reflect a correlation of DFNA36 phenotype with TMC1 genotype.

Two novel point mutations in the long‐range SHH enhancer in three families with triphalangeal thumb and preaxial polydactyly

Spatio-temporal expression of sonic hedgehog (SHH) is driven by a regulatory element (ZRS) that lies 1 Mb upstream from SHH. Point mutations within the highly conserved ZRS have been described in the hemimelic extra toes mouse and in four families with preaxial polydactyly [Lettice et al., 2003]. Four North American Caucasian families were identified with autosomal dominant triphalangeal thumb. DNA from 20 affected and 36 unaffected family members was evaluated by sequence analysis of a 774-bp highly conserved ZRS contained within LMBR1 intron 5. Mutations within ZRS were identified in three of four families. In pedigree A and C, a novel A/G transition was identified near the 5' end of ZRS at bp 739 that segregated with disease or carrier status. Pedigree A, described previously [Dobbs et al., 2000], is a large family with 19 affected members who exhibit a milder phenotype, including predominantly triphalangeal thumbs and low penetrance (82%) relative to other families. Pedigree C is a small family with two affected family members with triphalangeal thumb, and one affected with both triphalangeal thumb and preaxial polydactyly. A novel C/G mutation at bp 621 was identified in pedigree B that segregated with the disease in all four affected individuals who manifested both preaxial polydactyly and triphalangeal thumb. Both mutations alter putative Cdx transcription factor binding sites. Mutations within ZRS appear to be a common cause of familial triphalangeal thumb and preaxial polydactyly. A genotype/phenotype correlate is suggested by pedigree A, whose mutation lies near the 5' end of ZRS; this family demonstrates a higher rate of nonpenetrance and milder phenotype. However, modifier genes may be contributing to the milder phenotype in this family.

Relative Contribution of Genetic and Nongenetic Modifiers to Intestinal Obstruction in Cystic Fibrosis

Neonatal intestinal obstruction (meconium ileus [MI]) occurs in 15% of patients with cystic fibrosis (CF). Our aim was to determine the relative contribution of genetic and nongenetic modifiers to the development of this major complication of CF. A total of 65 monozygous twin pairs, 23 dizygous twin/triplet sets, and 349 sets of siblings with CF were analyzed for MI status, significant covariates, and genome-wide linkage. Specific mutations in the CF transmembrane conductance regulator (CFTR), the gene responsible for CF, correlated with MI, indicating a role for CFTR genotype. Monozygous twins showed substantially greater concordance for MI than dizygous twins and siblings (P = 1 x 10(-5)), showing that modifier genes independent of CFTR contribute substantially to this trait. Regression analysis revealed that MI was correlated with distal intestinal obstruction syndrome (P = 8 x 10(-4)). Unlike MI, concordance analysis indicated that the risk for development of distal intestinal obstruction syndrome in CF patients is caused primarily by nongenetic factors. Regions of suggestive linkage (logarithm of the odds of linkage >2.0) for modifier genes that cause MI (chromosomes 4q35.1, 8p23.1, and 11q25) or protect from MI (chromosomes 20p11.22 and 21q22.3) were identified by genome-wide analyses. These analyses did not support the existence of a major modifier gene on chromosome 19 in a region previously linked to MI. The CFTR gene along with 2 or more modifier genes are the major determinants of intestinal obstruction in newborn CF patients, whereas intestinal obstruction in older CF patients is caused primarily by nongenetic factors.

SNPs in the neural cell adhesion molecule 1 gene (NCAM1) may be associated with human neural tube defects

Neural tube defects (NTDs) are common birth defects, occurring in approximately 1/1,000 births; both genetic and environmental factors are implicated. To date, no major genetic risk factors have been identified. Throughout development, cell adhesion molecules are strongly implicated in cell-cell interactions, and may play a role in the formation and closure of the neural tube. To evaluate the role of neural cell adhesion molecule 1 (NCAM1) in risk of human NTDs, we screened for novel single-nucleotide polymorphisms (SNPs) within the gene. Eleven SNPs across NCAM1 were genotyped using TaqMan. We utilized a family-based approach to evaluate evidence for association and/or linkage disequilibrium. We evaluated American Caucasian simplex lumbosacral myelomeningocele families (n=132 families) using the family based association test (FBAT) and the pedigree disequilibrium test (PDT). Association analysis revealed a significant association between risk for NTDs and intronic SNP rs2298526 using both the FBAT test (P=0.0018) and the PDT (P=0.0025). Using the HBAT version of the FBAT to look for haplotype association, all pairwise comparisons with SNP rs2298526 were also significant. A replication study set, consisting of 72 additional families showed no significant association; however, the overall trend for overtransmission of the less common allele of SNP rs2298526 remained significant in the combined sample set. In addition, we analyzed the expression pattern of the NCAM1 protein in human embryos, and while NCAM1 is not expressed within the neural tube at the time of closure, it is expressed in the surrounding and later in differentiated neurons of the CNS. These results suggest variations in NCAM1 may influence risk for human NTDs.

Early onset and rapid progression of dominant nonsyndromic DFNA36 hearing loss.

To characterize the auditory and vestibular phenotype of autosomal dominant nonsyndromic DFNA36 hearing loss. Clinical evaluation of individuals with DFNA36 hearing loss linked to the D572N mutation of transmembrane channel-like gene 1 (TMC1). Medical history interviews, physical examinations, and pure-tone air conduction audiometry were performed in the field. Audiology and radiology reports were available and retrospectively reviewed for a subset of subjects. Primary, secondary, and tertiary referral centers (retrospectively reviewed studies); subjects' homes (prospective clinical evaluations). Thirteen affected members of a North American Caucasian family segregating DFNA36 hearing loss. Pure-tone audiometric thresholds and their rates of progression. Subjects had bilateral, symmetric, sensorineural hearing loss with a postlingual onset in the first decade of life. High frequencies were initially affected, followed by rapid progression (5.9 dB/yr for the 0.5/1/2/4-kHz pure-tone average) to profound deafness across all frequencies by the second decade of life. Two individuals had excellent auditory-verbal communication after rehabilitation with cochlear implants placed over two decades after total deafening. DFNA36 has one of the earliest onsets and most rapid rates of progression among the autosomal dominant non-syndromic hearing loss phenotypes. These distinctive features should facilitate its clinical detection and the development of clinical-molecular genetic diagnostic algorithms for dominant nonsyndromic hearing loss.

Genetic predisposition to external apical root resorption in orthodontic patients: linkage of chromosome-18 marker.

External apical root resorption (EARR) is a common orthodontic treatment sequela. Previous studies implicate a substantial genetic component for EARR. Using a candidate gene approach, we investigated possible linkage of EARR associated with orthodontic treatment with the TNSALP, TNFalpha, and TNFRSF11A gene loci. The sample was comprised of 38 American Caucasian families with a total of 79 siblings who completed comprehensive orthodontic treatment. EARR was assessed by means of pre- and post-treatment radiographs. Buccal swab cells were collected for extraction and analysis of DNA. No evidence of linkage was found with EARR and the TNFalpha and TNSALP genes. Non-parametric sibling pair linkage analysis identified evidence of linkage (LOD = 2.5; p = 0.02) of EARR affecting the maxillary central incisor with the microsatellite marker D18S64 (tightly linked to TNFRSF11A). This indicates that the TNFRSF11A locus, or another tightly linked gene, is associated with EARR.

Updated investigations of the role of methylenetetrahydrofolate reductase in human neural tube defects.

Folate supplementation appears to reduce the risk for neural tube defects (NTDs). Methylenetetrahydrofolate reductase (MTHFR) is a candidate gene in the folate metabolism pathway that has been extensively studied in different human populations. We examined the risk associated with having the thermolabile variant (TT) of MTHFR in a study of 175 American Caucasians with NTDs and their families. We found a significant association in patients compared with 195 unrelated controls [odds ratio (OR) = 2.13, 95% confidence interval (95% CI) = 1.11-4.09)], but not in mothers (OR = 1.29, 95% CI = 0.622-2.67) or in fathers (OR = 1.45, 95% CI = 0.681-3.09). We found no evidence for unequal transmission from parents to an affected child (p > 0.10). We failed to find a previously reported association for a combined haplotype for MTHFR and cystathionine beta-synthase, except in subjects with NTDs compared with 559 pooled controls (OR = 2.87, 95% CI = 1.03-8.03). We found no evidence for an association for a novel CA-repeat polymorphism identified in a gene closely linked to MTHFR (p > 0.10). Our studies continue to suggest that additional candidate genes other than MTHFR may be responsible for an increased risk to NTD in some American Caucasian families.

Cardiac amyloidosis associated with the transthyretin Ile122 mutation in a Caucasian family

The Ile 122 transthyretin variant associated with restrictive cardiomyopathy has been described in African-Americans and estimated to be present in approximately 4% of the Black population. We report the first American-Caucasian family with cardiomyopathy due to the TTR lie122 mutation. The high prevalence of this mutation in the Black population and the discovery that it may cause disease in other ethnic populations highlights the importance of considering this autosomal dominant systemic amyloidosis in all individuals with restrictive cardiomyopathy. Inadequate diagnosis combined with inappropriate treatment may have a significant impact on morbidity and mortality.

Linkage and Association between Inflammatory Bowel Disease and a Locus on Chromosome 12

Genetic epidemiological studies have shown that genetic factors are important in the pathogenesis of the idiopathic inflammatory bowel diseases (IBD), Crohn disease (CD), and ulcerative colitis (UC). A genome screen in the United Kingdom found linkage of IBD to a 41-cM region of chromosome 12, surrounding D12S83. We aimed to replicate this linkage and to narrow the region of interest. Nonparametric linkage analyses at microsatellites surrounding D12S83 were performed in 122 North American Caucasian families containing 208 genotyped IBD-affected relative pairs. Transmission/disequilibrium tests (TDTs) were also performed. We confirmed that IBD is linked to chromosome 12 (peak GENEHUNTER-PLUS LOD* score 2.76 [P = .00016] between D12S1724 and D12S90). The evidence for linkage is contributed by both the group of CD-affected relative pairs (peak GENEHUNTER-PLUS LOD* score 1.79 [P = .0021] between D12S1724 and D12S90) and the group of UC-affected relative pairs (peak GENEHUNTER-PLUS LOD* score 1.82 [P = .0019] at D12S335). The TDT is positive at the D12S83 locus (global chi2 = 16.41, 6 df, P = .012). In conclusion, we have independently confirmed linkage of IBD to the chromosome 12 region that we investigated. A positive TDT at D12S83 suggests that we have greatly narrowed the chromosome 12 region that contains an IBD locus.

Clinical Heterogeneity Associated with the Mitochondrial DNA C3303T Point Mutation ♦ 734

Dysfunction of mitochondria can affect all tissues and organs, especially those that depend heavily upon oxidative metabolism as the main energy source. In particular, evidence is accumulating that adequate mitochondrial function is critical to normal cardiac metabolism and that mutations in mitochondrial DNA (mtDNA) can result in severe cardiac disease. Cardiac involvement is frequent in mitochondrial disorders and, in some cases, biochemical studies have shown defects of the respiratory chain complexes and molecular studies have identified mtDNA mutations. In 1994, we reported a C3303T mutation in the mitochondrial tRNA Leu(UUR) gene in a family with cardiopathy and myopathy (Silvestri et al; Hum Mut 3:37). Although the mutation satisfied many of the generally accepted criteria for pathogenicity, its causative role remained uncertain because it had been described in a single family. Here we report four new unrelated families with the C3303T mutation who presented with clinical phenotypes ranging from isolated cardiopathy to isolated myopathy to a combination of cardiopathy and myopathy. Case 1 is an infant from an American Caucasian family who died with cardiomyopathy, with the mother and siblings asymptomatic at this time. Case 2 is a 1 year-old boy from an American family of Irish descent with cardiopathy; again, mother and an older sister are asymptomatic. Case 3 is a 4 year-old boy from an Australian family with myopathy. Cases 4-7 are members of a Chilean family where a 10 year-old girl and her maternal grandmother presented with cardiopathy and myopathy while her mother and her maternal uncle have isolated myopathy. Our findings confirm the pathogenicity of the C3303T mutation, suggest that it is not rare and is present in individuals from various ethnic backgrounds, and that it can have a heterogeneous clinical presentation. However, the pathogenic mechanism(s) by which this mutation causes disease remain to be elucidated. It is important to consider the C3303T mutation in the differential diagnosis of familial cardiomyopathies, especially when there is evidence of maternal inheritance.

Molecular and clinical findings in a family with dentatorubral‐pallidoluysian atrophy

Herein we describe the molecular and clinical findings in a North American Caucasian family with dentatorubral-pallidoluysian atrophy (DRPLA). These patients all presented with an autosomal dominant neurodegenerative disorder characterized by a variable combination of clinical symptoms including seizures, ataxia, dementia, choreiform movements, mental retardation, and psychiatric disease. Neuroradiologic findings in the index case revealed deep subcortical white matter changes on magnetic resonance imaging. Prior to referral, the family carried a diagnosis of Huntington's disease (HD). Subsequent direct molecular testing for HD failed to identify the HD expansion mutation in affected individuals. Molecular testing for DRPLA, however, demonstrated the presence of the recently characterized DRPLA expansion mutation in all affected individuals. The size of the expansion correlated with the age of onset of clinical symptoms. As DRPLA has rarely been reported in North American and European populations, the molecular confirmation of DRPLA in this family provides support for the hypothesis that DRPLA may not be as geographically restricted as once thought.

Association between a T cell receptor restriction fragment length polymorphism and systemic lupus erythematosus.

The present study was designed to test the possibility that T cell receptor genes are associated/linked to those involved in systemic lupus erythematosus (SLE). Genomic DNA was isolated from 31 unrelated Caucasian SLE patients, 34 unrelated Caucasian normals, 5 multiplex American Caucasian SLE families, 9 multiplex Mexican SLE families, and 13 unrelated Mexican normals. The DNA was digested with Pst I, electrophoresed, and transferred to membranes by the Southern blot method. The blots were probed with a cDNA probe for the alpha chain of the T cell receptor. 13 polymorphic RFLP patterns were recognized. 1.3- and 3.0-kb band pairs were observed in 15 of 31 of American Caucasian patients and 4 of 34 American Caucasian controls (chi square, 8.81; P less than 0.002; relative risk, 7); there was no association of any RFLP pattern with Mexican SLE. The cDNA probe was cut with Rsa I, EcoR I, and Ava II into fragments corresponding to the V, J, C, and 3'UT regions. Only the fragment corresponding to the constant region reacted with the 1.3/3.0-kb band pair. These observations suggest that a genetic marker of the constant region of the alpha chain of the T cell receptor is associated with genes involved in SLE.

The inheritance of digital dermatoglyphic patterns in 54 American Caucasian families.

We searched for single gene effects in determining digital patterns and compared with the evidence for monogenic determination in Israelis (Slatis et al., '76). Our subjects were 108 parents from central Louisiana and 123 of their offspring; there were 127 females and 104 males ranging in age from eight to 66 years. Arches on the thumb--Among 11 subjects, two were bilateral, and three pairs were related, two as parent-child and one as sib-sib; the findings support the concept of an incompletely penetrant dominant gene. Radial loops on the thumb--three occurred unilaterally in unrelated subjects. Ulnar loops (U) and whorls (W) on the thumb--Phenotype frequency was 104 UU, 65 UW, 47 WW, 15 other. The proportion of UU offspring was highest with both UU parents and diminished as the parents had increasingly more W, supporting the single locus hypothesis. Arches (A) on the fingers--71 A, 160 non-A showed a greater A frequency than in the Israelis. The proportion of A offspring was highest with both A parents and diminished as the parents became non-A. Sequence WWUWW--Among nine subjects, one was bilateral, two left, and six right; two pairs related as parent-child and sib-sib. Sequence WUUWW--Among five subjects, one was bilateral, and three were related as parent-offspring. Radial loops on index fingers--Frequency of 32% was greater than in the Israelis. Middle fingers--86% were U, 73% being bilateral. Radial loops on ring and little fingers--Among eight unilateral subjects, none was related. Ulnar loops and whorls on ring fingers--Proportion of UU offspring was greatest with both UU parents and diminished as parents became WW. We conclude that the Louisianians showed evidence for single gene effects similar to that of the Israelis.

The inheritance of palmar and hallucal dermatoglyphic patterns in fifty-four American Caucasian families.

We searched for single gene effects determining certain palmar and plantar patterns - two interdigital and the hypothenar areas, palmar main line sequence, and hallucal pattern. Our subjects were 108 parents from central Louisiana and 123 of their offspring; there were 127 females and 104 males. For the third and fourth interdigital areas, we classified for presence of a pattern (+) or no pattern (-). For the hypothenar area, we classified arch, anteform, and open field as no pattern (-) and other configurations as a pattern (+). Main line sequence we determined by the distal to proximal ordering of the five main lines. We analyzed the hallucal area by combining three loop patterns. Segregational analyses followed. For the third interdigital area, the frequency of + was 51%. For the fourth interdigital area, the frequency of + was 45%. We set out the six mating types by the bilateral occurence of pattern in each area and found similar results. The proportion of ++ offspring was highest with both ++ parents and diminished as the parents became increasingly more --. Evidence for genetic determination of six different main line sequences consisted of the proportion of related/(related + unrelated) which averaged 0.48. Parent-offspring occurrence of an accessory triradius and absence of the c triradius suggested monogenic control. Segregation of the hallucal patterns was less suggestive. We conclude that the results offer evidence for substantial genetic determination of palmar dermatoglyphics, and for some patterns possible monogenic determination.

Hemoglobin J in an American Caucasian Family of Swedish Ancestry

Abstract Two instances of the heterozygous state of hemoglobin J are described in the male members of an American Caucasian family of Swedish ancestry.