Small Pedigrees Research Articles

Coding and Noncoding Variation of the Human Calcium-Channel β 4-Subunit Gene CACNB4 in Patients with Idiopathic Generalized Epilepsy and Episodic Ataxia

Inactivation of the beta4 subunit of the calcium channel in the mouse neurological mutant lethargic results in a complex neurological disorder that includes absence epilepsy and ataxia. To determine the role of the calcium-channel beta4-subunit gene CACNB4 on chromosome 2q22-23 in related human disorders, we screened for mutations in small pedigrees with familial epilepsy and ataxia. The premature-termination mutation R482X was identified in a patient with juvenile myoclonic epilepsy. The R482X protein lacks the 38 C-terminal amino acids containing part of an interaction domain for the alpha1 subunit. The missense mutation C104F was identified both in a German family with generalized epilepsy and praxis-induced seizures and in a French Canadian family with episodic ataxia. These coding mutations were not detected in 255 unaffected control individuals (510 chromosomes), and they may be considered candidate disease mutations. The results of functional tests of the truncated protein R482X in Xenopus laevis oocytes demonstrated a small decrease in the fast time constant for inactivation of the cotransfected alpha1 subunit. Further studies will be required to evaluate the in vivo consequences of these mutations. We also describe eight noncoding single-nucleotide substitutions, two of which are present at polymorphic frequency, and a previously unrecognized first intron of CACNB4 that interrupts exon 1 at codon 21.

Ovarian differentiation and gonadal failure.

Ovarian failure can result from several different genetic mechanisms-X chromosomal abnormalities, autosomal recessive genes causing various types of XX gonadal dysgenesis, and autosomal dominant genes. The number and precise location of loci on the X are still under investigation, but it is clear that, in aggregate, these genes are responsible for ovarian maintenance, given that monosomy X shows germ cells that undergo accelerated atresia. Despite recent hypotheses, at present there is no evidence for a gene directing primary ovarian differentiation; this process may be constitutive. Phenotypic/karyotypic correlation and limited molecular confirmation have long shown that proximal Xp and proximal Xq contain regions of the most importance to ovarian maintenance. Terminal deletions at Xp11 result in 50% primary amenorrhea and 50% premature ovarian failure or fertility. Deletions at Xq13 usually produce primary amenorrhea. Terminal deletions nearer the telomeres on either Xp of Xq bring about premature ovarian failure more often than complete ovarian failure. The X-linked zinc finger gene (ZFX) and diaphanous 2 Drosophila homologue (DIAPH2) are the only candidate genes for ovarian maintenance that map to the X chromosome. Additional, as yet unidentified, genes along the X chromosome must be involved. The search for these genes in humans is hampered by the lack of candidate genes that map to the X chromosome, the scarcity of patients with fortuitous autosomal translocations, and small pedigrees, which hinder mapping of the loci. In addition, difficulties with human germ cell research also make it challenging to dissect genes important to ovarian development. Autosomal genes also are involved in ovarian differentiation and gonadal failure. Follicle-stimulating hormone receptor and ataxia telangiectasia are examples of autosomal genes known to cause human ovarian failure. Transgenic mouse models point to many other candidate autosomal genes, and sequencing of the human homologues in affected women should lead to the discovery of new genes responsible for human ovarian failure. Identification, functional analysis, and mapping of novel genes specifically expressed in the ovary of mice and women eventually should lead to fruitful dissection of essential genes in mammalian ovarian development and maintenance.

Autosomal Recessive Hereditary Motor and Sensory Neuropathy with Focally Folded Myelin Sheaths (CMT4B).

Hereditary motor and sensory neuropathy with focally folded myelin sheaths, or Charcot-Marie-Tooth neuropathy type 4B (CMT4B), is a distinct clinical and genetic entity belonging to the heterogeneous group of autosomal recessive demyelinating neuropathies. We first described a large inbred pedigree with 10 patients affected by CMT4B, which enabled us to uncover the genetic findings, clinical spectrum, and natural history of such a disorder. The clinical picture was characterized by infantile onset with progressive symmetric distal and proximal muscular weakness. Using homozygosity mapping and haplotype sharing analysis, we found evidence of linkage to chromosome 11q23. We then identified a second unrelated family in which two individuals were affected with CMT4B. Although the clinical findings were similar to those previously reported, we excluded the disease locus segregating in this smaller pedigree from the 11q23 region. We thus provided evidence for a second locus causing the CMT4B phenotype. All these findings indicate that CMT4B seems to be phenotypically quite homogeneous, but is genetically heterogeneous.

Periventricular Heterotopia and the Genetics of Neuronal Migration in the Cerebral Cortex

In recent years, remarkable contributions to our understanding of how the brain develops have come from the field of genetics. The study of brain development is important, not only to further our understanding of this complex phenomenon, but because gross brain malformations are now recognized to cause significant proportions of cognitive and neurologic disorders. When the cerebral cortex fails to form properly, the result is often severe mental retardation. Even mild dysgenesis of the cortex is frequently associated with epilepsy.

Ascertainment Corrections Based on Smaller Family Units

Ascertainment concerns the manner by which families are selected for genetic analysis and how to correct for it in likelihood models. Because such families are often neither drawn at random nor selected according to well-defined rules, the problem of ascertainment correction in the genetic analysis of family data has proved durable. This paper undertakes a systematic study of ascertainment corrections in terms of smaller distinct units, which will usually be sibships, nuclear families, or small pedigrees. Three principal results are presented. The first is that ascertainment corrections in likelihood models for family data can be made in terms of smaller units, without breaking up the pedigree. The second is that the appropriate correction for single ascertainment in a unit is the reciprocal of the sum of the marginal probabilities of all the persons relevant to its ascertainment, as if affected. The third result is a generalization of the single ascertainment-correction formula to k-plex ascertainment, in which each unit has k or more affecteds. The correction is the reciprocal of the sum of the joint probabilities of all distinct sets of k persons in the unit, as if they were all affected. In extended families, two additional ascertainment schemes will be considered and explicit formulas will be presented. One of these schemes is "uniform-proband-status ascertainment," in which nonmembers of a given unit have the same chance as members to become probands if they are affected; the other scheme is the "inverse law of ascertainment," in which the chance that nonmembers of a unit will become probands for that unit decreases with degree of relationship. Several specific recommendations are made for further study.

Linkage of Gordon's syndrome to the long arm of chromosome 17 in a region recently linked to familial essential hypertension.

Gordon's syndrome (GS) is a salt-sensitive, hyperkalaemic, familial hypertension syndrome which may masquerade in milder forms as essential hypertension. The response of hyperakalaemia to dietary salt restriction and to mineralocorticoids is heterogeneous, suggesting genetic heterogeneity. In a recently published study using small pedigrees, possible linkage of GS to chromosomes 1 and 17 was described. Studying the largest pedigree so far reported with GS, and using fluorescent-labelled microsatellite markers, we sought evidence of linkage to chromosomes 1 and 17. In this family there was no segregation of GS with any of the markers for chromosome 1. On chromosome 17, however, evidence of linkage was found with a maximum multipoint LOD score of 2.4 (the maximum LOD possible from the pedigree) over markers D17S250 and D17S934. This represents strong evidence in this pedigree for a responsible gene mutation on the long arm of chromosome 17. Recent reports of linkage for essential hypertension and, especially, familial essential hypertension within the same area of chromosome 17 containing the D17S934 marker raise the possibility that the same gene may be responsible for familial essential hypertension and for Gordon's syndrome.

Multipoint Quantitative-Trait Linkage Analysis in General Pedigrees

Multipoint linkage analysis of quantitative-trait loci (QTLs) has previously been restricted to sibships and small pedigrees. In this article, we show how variance-component linkage methods can be used in pedigrees of arbitrary size and complexity, and we develop a general framework for multipoint identity-by-descent (IBD) probability calculations. We extend the sib-pair multipoint mapping approach of Fulker et al. to general relative pairs. This multipoint IBD method uses the proportion of alleles shared identical by descent at genotyped loci to estimate IBD sharing at arbitrary points along a chromosome for each relative pair. We have derived correlations in IBD sharing as a function of chromosomal distance for relative pairs in general pedigrees and provide a simple framework whereby these correlations can be easily obtained for any relative pair related by a single line of descent or by multiple independent lines of descent. Once calculated, the multipoint relative-pair IBDs can be utilized in variance-component linkage analysis, which considers the likelihood of the entire pedigree jointly. Examples are given that use simulated data, demonstrating both the accuracy of QTL localization and the increase in power provided by multipoint analysis with 5-, 10-, and 20-cM marker maps. The general pedigree variance component and IBD estimation methods have been implemented in the SOLAR (Sequential Oligogenic Linkage Analysis Routines) computer package.

Bipolar affective disorder partially cosegregates with a balanced t(9;11)(p24;q23.1) chromosomal translocation in a small pedigree

Bipolar affective disorder partially cosegregates with a balanced t(9;11)(p24;q23.1) chromosomal translocation in a small pedigree

Bipolar affective disorder partially cosegregates with a balanced t(9;11)(p24;q23.1) chromosomal translocation in a small pedigree

Analysis of an extended pedigree in which a balanced t(9;11)(p24;q23.1) translocation was found to cosegregate with bipolar affective disorder revealed that five of 11 translocation carriers had bipolar affective disorder and one carrier had unipolar depression. There were no affected individuals in the pedigree without the balanced translocation. We hypothesized that gene(s) or gene regulatory regions disrupted by the translocation might be contributing to the bipolar affective disorder in a dominant fashion. To test this hypothesis, we isolated the derivative chromosome 9 and derivative chromosome 11 in somatic cell hybrids and identified the nearest flanking markers on chromosome 9 (D9S230 and D9S2011E/HRFX3) and chromosome 11 (EST00652 and CRYA2). YAC contigs were constructed in the region of flanking markers for both chromosomes 9 and 11. Chromosome 11 breakpoint was localized within an 8-kb region in a small insert (100 kb) YAC. Chromosome 9 breakpoint was localized within approximately 2 Mb region. Several genes and ESTs including EST00652, CRYA2, DRD2, 5HTR3 on chromosome 11 and VLDLR and SLC1A1 on chromosome 9 were mapped within the vicinity of the breakpoint but were shown not to be disrupted by the translocation breakpoint. Although several possibilities exist regarding the role of the balanced translocation in developing bipolar affective disorder in this pedigree, including a chance cosegregation, identification of a disrupted gene or gene regulatory region with the help of physical mapping resources described in this study may help to identify the presence of a susceptibility gene for this disorder.

Familial hyperinsulinism with apparent autosomal dominant inheritance: Clinical and genetic differences from the autosomal recessive variant

We describe three families with hypoglycemia caused by familial hyperinsulinism (HI) in whom vertical transmission of the disorder occurred, suggesting autosomal dominant (AD) inheritance. We therefore examined the relationship between the apparent AD disorder and the more common autosomal recessive (AR) form of HI, which has recently been linked to the sulfonylurea receptor on chromosome 11p15.1. The clinical features of the 11 patients with AD HI were milder than those seen in 14 patients with AR HI. Hypoglycemia was readily controlled with either diet alone or with diazoxide in 10 of 11 patients with AD HI but in none of those with the AR form. In one large pedigree, analysis of genomic DNA with polymorphic simple sequence repeat markers excluded linkage of AD HI to the SUR locus in a dominant manner. The possibility of linkage to the SUR locus could not be absolutely excluded in the two smaller pedigrees. None of the published mutations of the SUR gene identified in patients with AR HI were detected in the patients with the AD form. We conclude that the AD form of hyperinsulinism is phenotypically different from the AR variant. The identification of more families with this form of HI may make it possible to locate the responsible gene by the use of linkage analysis. (J Pediatr 1998;132:9-14)

An approximation to the likelihood for a pedigree with loops

This paper presents a new approximation to the likelihood for a pedigree with loops, based on cutting all loops and extending the pedigree at the cuts. An opimum loop-cutting strategy and an iterative extension technique are presented. The likelihood for a pedigree with loops is then approximated by the conditional likelihood for the entire cut-extended pedigree given the extended part. The approximate likelihoods are compared with the exact likelihoods obtained using the program MENDEL for several small pedigrees with loops. The approximation is efficient for large pedigrees with complex loops in terms of computing speed and memory requirements.

Linkage analysis in three families with nonspecific X-linked mental retardation.

Nonspecific X-linked mental retardation (XLMR) is a common disorder. The number of genes involved in this condition is not known, but it is estimated to be more than 10. We present a clinical and linkage study on 3 families with XLMR. All families were analyzed using highly polymorphic markers covering the X chromosome; screening for the fragile X mutation was negative. The first family (MRX 36) consisted of 1 female and 4 male patients in 3 generations and 7 healthy individuals. Considering the female as an expressing heterozygous carrier, a maximum LOD score of 3.41 was reached in region Xp21.2-Xp22.1. Considering her phenotype to be unknown, a LODmax of 1.97 was reached in the same region. The second family consisted of 5 affected and 6 healthy males with mild to borderline mental retardation. Linkage analysis using an X-linked recessive model with full penetrance and no phenocopies excluded linkage over almost the entire X chromosome. Using alternative models, including an affecteds-only analysis, a LODmax of 1.49 was found in region Xq24-28. The third family, consisting of 4 male patients with moderate mental retardation in 1 generation yielded a LODmax of 0.9 in region Xp22.13-11.3. However, even in this small pedigree, exclusion mapping was able to exclude very large parts of the X chromosome and in this way identify a likely candidate region.

Linkage analysis in three families with nonspecific X‐linked mental retardation

Nonspecific X-linked mental retardation (XLMR) is a common disorder. The number of genes involved in this condition is not known, but it is estimated to be more than 10. We present a clinical and linkage study on 3 families with XLMR. All families were analyzed using highly polymorphic markers covering the X chromosome; screening for the fragile X mutation was negative. The first family (MRX 36) consisted of 1 female and 4 male patients in 3 generations and 7 healthy individuals. Considering the female as an expressing heterozygous carrier, a maximum LOD score of 3.41 was reached in region Xp21.2–Xp22.1. Considering her phenotype to be unknown, a LODmax of 1.97 was reached in the same region. The second family consisted of 5 affected and 6 healthy males with mild to borderline mental retardation. Linkage analysis using an X-linked recessive model with full penetrance and no phenocopies excluded linkage over almost the entire X chromosome. Using alternative models, including an affecteds-only analysis, a LODmax of 1.49 was found in region Xq24–28. The third family, consisting of 4 male patients with moderate mental retardation in 1 generation yielded a LODmax of 0.9 in region Xp22.13–11.3. However, even in this small pedigree, exclusion mapping was able to exclude very large parts of the X chromosome and in this way identify a likely candidate region. © 1996 Wiley-Liss, Inc.

The effect of family size on estimates of the frequency of hereditary non-polyposis colorectal cancer.

Diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) is currently based on phenotypical analysis of an expanded pedigree. Diagnostic guidelines ('Amsterdam criteria') proposed by the International Collaborative Group on HNPCC are often too stringent for use with small families. There is also the possibility of false-positive diagnosis in large pedigrees that may contain chance clusters of tumours. This study was conducted to determine the effect of family size on the probability of diagnosing HNPCC according to the Amsterdam criteria. A total of 1052 patients with colorectal cancer were classified as HNPCC or non-HNPCC according to the Amsterdam criteria. Associations between this diagnosis and the size of the first-degree pedigree were evaluated in logistic regression and linear discriminant analyses. Logistic regression showed a significant association for family size with the Amsterdam-criteria-based HNPCC diagnosis. Linear discriminant analysis showed that HNPCC diagnosis was most likely to occur when first-degree pedigrees contained more than seven relatives. Failure to consider family size in phenotypic diagnosis of HNPCC can lead to both under- and overestimation of the frequency of this disease. Small pedigrees must be expanded to reliably exclude HNPCC. Positive diagnoses based on assessment of eight or more first-degree relatives should be supported by other clinical features.

Molecular diagnostic tests for ascertainment of genotype at the rod cone dysplasia 1 (rcd1) locus in Irish setters.

Rod-cone dysplasia type 1 (rcd1) is one of several canine photoreceptor degenerations, collectively termed progressive retinal atrophy (PRA), that afflict different breeds of dogs. The rcd1 phenotype is an early onset autosomal recessive disease caused by a nonsense amber mutation, at codon 807, in the canine gene for the beta-subunit of rod cyclic GMP phosphodiesterase (canine PDEB). The mutation involves a G to A transition at nucleotide position 2420, which presumably would cause premature termination of the canine PDEB protein by 49 amino acid residues. In both a small pedigree study of Irish setters from the United Kingdom and in larger canine pedigree studies in the United States, this gene defect has been found to be the only mutation causing rcd1. Here we report development of a diagnostic test which unequivocally distinguishes the three genotypes at the rcd1 locus: rcd1/rcd1 (homozygous mutant, affected); rcd1/+ (heterozygous, carrier); and +/+ (homozygous normal, wildtype).

Monte Carlo Estimation of Mixed Models for Large Complex Pedigrees

In human quantitative genetics, computational complexity restricts the current methods for estimation of mixed models that include major gene effects to data on small pedigrees. However, large complex pedigrees are not uncommon in practice. Also, large pedigrees tend to provide more information on genetic transmission and are more genetically homogeneous than a pooled sample of many nuclear families. We present a Monte Carlo method, using jointly the EM algorithm and the Gibbs sampler, for estimation of mixed models. The approach also provides a Monte Carlo estimate of the asymptotic variance-covariance matrix of the parameters. The methods are conceptually simple, easy to implement, and can handle multiple heritable/nonheritable random components. A numerical example is given to illustrate the methods.

Assignment of Granular Corneal Dystrophy Groenouw Type I (CDGG1 ) to Chromosome 5q

Granular corneal dystrophy Groenouw type I (CDGG1) is an autosomal dominant disease with complete penetrance. 124 blood samples were collected from a single Danish pedigree of seven generations. Linkage was discovered with markers on chromosome 5q, with IL9 (Z = 15.96; theta M = 0.027, theta F = 0.00) and D5S436 (Z = 11.75; theta M = 0.00, theta F = 0.081) flanking the disease locus most closely. The marker IL9 is located in the region 5q22-q32. By multilocus linkage analysis the most likely position of CDGG1 among 9 markers was: D5S396-IL9-CDGG1-D5S436-D5S210/D5S207++ +-D5S434-D5S119-D5S211 and CDGG1-D5S402-D5S434. In each of two independent small pedigrees, in which a milder form of CDGG1 occurs, the disease gene was also linked to IL9 (Z = 3.02 at theta = 0.0 in males and females); i.e. the severe and the milder forms may be allelic.

Genetic evaluation of pedigree beef cattle in Great Britain

In order that genetic progress in British beef breeds could be improved, performance traits have been recorded by the Meat and Livestock Commission for many years. A large number of pedigree beef herds have recorded with the Meat and Livestock Commission during this period. Until recently, these records were only made use of via within herd contemporary comparisons such that the results for animals could not be compared across herds or time.Through the use of Individual Animal Model Best Linear Unbiased Prediction (BLUP), differences between herds and contemporary groups within herds can be accounted for provided there are genetic links between herds and contemporary groups. As a result of the small pedigree herd size in Great Britain, typically less than 20, sires are often chosen from outside the herd in order to reduce inbreeding. This practise has resulted in there being a relatively high level of connectedness between contemporary groups and this enables the BLUP procedure to disentangle management and genetic effects.

The relative efficiency and power of small-pedigree studies of the heritability of a quantitative trait.

Methods to determine the proportion of variability manifested by a quantitative trait that is attributable to additive genetic effects are important tools for human population and statistical geneticists. Though traditional methods based on parent-offspring and sib-pair correlations have been well researched, they are being steadily supplanted or complemented by more powerful pedigree-based variance-component techniques. In this paper, a theoretical investigation of the relative efficiency and power of small (i.e., < 10 members) variance-component pedigree designs for heritability estimation is undertaken. The information gain in adding sibs and generations to pedigrees is discussed. Sample size guidelines based on theoretical power functions are offered, as are directions for future research.

Parasitic otitis in sheep associated with psoroptes infestation: a clinical and epidemiological study.

Parasitic otitis associated with psoroptes infestation was diagnosed in a small pedigree flock of sheep with aural haematomas, abscessation and cauliflower ears. Thirteen of the 15 lambs were affected but the clinical signs were mild; small, discrete, crusty lesions on the inner aspect of the ear at the junction of its anterior and posterior borders were typical. Nine of the 20 adults were affected but the lesions were more severe. Eighteen of the 64 members of the breed society who responded to a telephone survey reported sheep with similar clinical signs in their flocks. The proportion of animals affected ranged from 1 to 60 per cent with a median value of 16 per cent.