Family Pedigree Analysis Research Articles

Genetic Evaluation of Lipoprotein(a) in Intracranial Aneurysm Disease

Elevations in serum lipoprotein(a) [Lp(a)] levels have been reported in intracranial aneurysm (IA) disease. Our aim was to investigate a genetic basis for this observation. We performed a comparative analysis of size polymorphisms at two loci (kringle 4 [K4] and TTTTA pentanucleotide [PN] repeats) within the apolipoprotein(a) gene on Chromosome 6q26-27 among patients with sporadic IAs (n = 50), members of three IA families (n = 50), and control subjects (n = 50). There was no significant difference in mean Lp(a) levels between patients with sporadic IAs and control subjects, but IA family members exhibited a more than twofold elevation in mean Lp(a) levels, compared with control subjects (29.2 versus 12.9 mg %). Inverse relationships between K4/PN numbers and serum Lp(a) levels were demonstrated; genotype frequencies did not differ significantly from a Hardy-Weinberg equilibrium or from published frequencies for other Caucasian populations. We detected no difference in mean K4 and PN genotypic indices between patients with IAs and control subjects (9.3 and 16.92 versus 9.0 and 16.92, respectively), but IA families did exhibit a lower mean K4 genotypic index (7.7), compared with control subjects. Superficial analysis of family pedigrees revealed no suggestion of linkage between K4/PN genotypes and IA disease. The previously described elevation in Lp(a) levels among patients with sporadic IAs might be explained by an acute-phase response. Crude Lp(a) measurements might provide a useful predictive test for familial IA disease, but with the disadvantage of low specificity. The possibility of linkage of familial IA disease to a particular apolipoprotein(a) isoform size range has not been eliminated.

Molecular genetic, biochemical, and clinical studies in three families with cardiac Fabry’s disease

The variant form of Fabry’s disease, called cardiac Fabry’s disease, which has left ventricular hypertrophy as its main clinical manifestation is not uncommon. Because there has been no pedigree analysis in families with cardiac Fabry’s disease, we performed gene analyses, enzyme assays, and cardiac evaluations in 3 distinct families with cardiac Fabry’s disease. Gene analyses were performed in all 18 members of 3 families including 3 male probands. Five hemizygotes and 6 heterozygotes were identified. Plasma α-galactosidase A activity was measured in all 18 family members. Echocardiography and electrocardiography were performed in the 5 hemizygotes and in 5 of the 6 heterozygotes. The proband and 3 heterozygotes from a pedigree with a mutation in exon 6 of the α-galactosidase A sequence leading to a Met296Ile substitution showed a decrease in α-galactosidase A activity. In a separate pedigree, a proband and his hemizygous brother, with a mutation in exon 2 leading to a Glu66Gln substitution, had a decrease in α-galactosidase A activity, whereas 3 heterozygotes had normal values. In the third pedigree, a decrease in α-galactosidase A activity was observed in 2 hemizygotes who have a mutation in exon 1 leading to an Ala20Pro substitution. Although all 5 hemizygotes exhibited left ventricular hypertrophy on echocardiography, all 5 heterozygotes lacked this finding. Because plasma α-galactosidase A activity was normal in some heterozygotes with cardiac Fabry’s disease, gene analysis is essential for an accurate diagnosis. Patients with cardiac Fabry’s disease thus show an x-linked form of hypertrophic cardiomyopathy.

Mitochondrial DNA and disease

Mitochondrial DNA (mtDNA) defects are a relatively common cause of inherited disease and have been implicated in both ageing and cancer. MtDNA encodes essential subunits of the mitochondrial respiratory chain and defects result in impaired oxidative phosphorylation (OXPHOS). Similar OXPHOS defects have been shown to be present in a number of neurodegenerative conditions, including Parkinson’s disease, as well as in normal ageing human tissues. Additionally, a number of tumours have been shown to contain mtDNA mutations and an altered metabolic phenotype. In this review we outline the unique characteristics of mitochondrial genetics before detailing important pathological features of mtDNA diseases, focusing on adult neurological disease as well as the role of mtDNA mutations in neurodegenerative diseases, ageing and cancer. Copyright  2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Scanning the genome for essential hypertension loci.

1. Essential hypertension occurs in people with an underlying genetic predisposition who subject themselves to adverse environmental influences. The number of genes involved is unknown, as is the extent to which each contributes to final blood pressure and the severity of the disease. 2. In the past, studies of potential candidate genes have been performed by association (case-control) analysis of unrelated individuals or linkage (pedigree or sibpair) analysis of families. These studies have resulted in several positive findings but, as one may expect, also an enormous number of negative results. 3. In order to uncover the major genetic loci for essential hypertension, it is proposed that scanning the genome systematically in 100-200 affected sibships should prove successful. 4. This involves genotyping sets of hypertensive sibships to determine their complement of several hundred microsatellite polymorphisms. Those that are highly informative, by having a high heterozygosity, are most suitable. Also, the markers need to be spaced sufficiently evenly across the genome so as to ensure adequate coverage. 5. Tests are performed to determine increased segregation of alleles of each marker with hypertension. The analytical tools involve specialized statistical programs that can detect such differences. Non-parametric multipoint analysis is an appropriate approach. 6. In this way, loci for essential hypertension are beginning to emerge.

Absence of adult dental anomalies in familial hypophosphatasia.

This paper is a supplemental report on 3 previous publications about a family in which 3 male children manifested gingival recession, alveolar bone resorption and premature exfoliation of their deciduous teeth without apical root resorption and without clinical signs of inflammation. Laboratory blood and urine studies in conjunction with an analysis of periodontal microflora and family pedigrees established a diagnosis of hypophosphatasia in these 3 children, as well as their father, the paternal grandmother and paternal great-uncle. Clinical data also revealed that a son of the paternal great-uncle and his daughter were similarly affected. The family pedigree is consistent with an autosomal dominant mode of transmission. The 3 brothers are now between the ages of 18 and 22 yr and all have complete permanent dentitions. Aside from some periodontal manifestations of prior dentoalveolar trauma, most of the findings of the periodontal assessment are within normal limits. All 3 exhibit moderate to severe caries and some degree of gingival inflammation, but minimal periodontal pathosis.

Family pedigree analysis of children with severe breath-holding spells

We examined family pedigrees of children with severe breath-holding spells (SBHS). There were 57 probands (27 males, 30 females; 44 cyanotic, 13 pallid) whose families comprised 1683 individuals. We found that 31 (27%) of 114 proband parents and 9 (21%) of 43 proband siblings had current or prior SBHS. Father-to-son transmission was observed in 7 instances. There were 7 families with 2 or more affected siblings and 5 families with 3 or more affected members. From 85 nuclear families, 130 individuals had current or prior SBHS (59 males, 71 females; male/female ratio, 1:1.2). These data suggest that the most likely underlying genetic inheritance pattern in SBHS is an autosomal dominant trait with reduced penetrance. (J Pediatr 1997;130:647-51)

Pedigree analysis in families with febrile seizures.

Febrile seizures are the most common form of seizures, occurring in an estimated 2-5% of North American children. We carried out a systematic pedigree study of febrile seizure probands. Forty of 52 probands (77%) in a referral population selected for increased severity had more than one case per family: one family had 10 cases, one family had 7, 3 families had 6, 2 had 5, 3 had 4, 13 had 3, and 17 had 2 cases. Mode of inheritance in the multicase families best fit the hypothesis of autosomal dominance with reduced penetrance. Polygenic inheritance could not be excluded for some of the smaller families. There was no support for X-linked or mitochondrial inheritance. Penetrance was calculated to be 0.64. Because the cases were selected for increased severity, this represents a useful estimate of the upper limit of penetrance and is in agreement with twin studies. Simulated lod scores showed adequate power for a linkage study in the absence of heterogeneity. Individual families had simulated average lod scores as high as 2.1. However, with potential heterogeneity, assuming only 70% of families share the same disease locus, average lod scores were marginal, and a high density map of marker loci and additional families would be required to document linkage.

Pedigree analysis in families with febrile seizures

Pedigree analysis in families with febrile seizures

Hereditary dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a common and important cause of morbidity and mortality. Many factors can contribute to the development of this disorder, although most commonly the etiology is unexplained. However, recent studies in individuals with idiopathic DCM now reveal a heritable cause in 20-30% of individuals. Diverse modes of inheritance have been demonstrated, encompassing an autosomal dominant type (by far the most common), together with recessive and X-linked forms, and maternal inheritance through mitochondrial DNA. The hereditary forms of DCM (HDCM) predominantly affect the left ventricle, although inherited abnormalities affecting primarily the right ventricle also are described. HDCM may occur as a primary cardiomyopathy, or secondary to inherited systemic metabolic or neuromuscular disorders. The causative genes for primary HDCM of the autosomal dominant and recessive types have not yet been discovered, but the combination of family pedigree analysis and phenotyping by echocardiography, together with new genetic techniques, should now allow their identification. Knowledge of the gene or genes responsible for HDCM would improve diagnostic accuracy, facilitate genetic counseling, advance understanding of pathogenesis, and provide the starting point for new methods of treatment. Because of the frequently heritable nature of DCM, it is of great importance that a diligent search for all potentially affected family members be undertaken.

Population genetic and family studies on aldehyde dehydrogenase deficiency and alcohol sensitivity

Population genetic studies on the prevalence of aldehyde dehydrogenase isozyme I (ALDH I) deficiency in various Caucasian, Oriental, African, and American Indian subjects were carried out using hair roots as peripheral source of the enzyme activity. While a very high percentage of Orientals with Mongoloid origin were found deficient in ALDH I activity, no deficiency was detected in Caucasian and African populations. Native American Indians showed a relatively low incidence of ALDH I deficiency. A genetic model based on the phenotype determination using antisera purified human liver ALDH I is proposed. Pedigree analysis of Japanese families suggests an autosomal codominant mode of inheritance.

Segregation analyses of tooth size in a Melanesian population.

Dental casts and genealogical records collected among several linguistic groups of the Solomon Islands of Bougainville and Malaita form the data-base for the present series of analyses of the human dentition at the population level. Pedigree analysis and complex segregation analysis of nuclear families produce mutually consistent results which are interpreted as the absence of any significant major-gene effect on tooth size.