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Abstract Two cases of Cornelia de Lange syndrome with similar phenotypic features are reported. Key Words: Cornelia de Lange syndrome, Dwarfism Introduction Cornelia de Lange syndrome (CDLS), also known as [...]

ABSTRACT Acrogeria is one of the premature aging syndromes with an unknown mode of inheritance. Familial cases are quite rare. A report of the disease in a brother and sister [...]

Code Number: dv03003 Abstract Severe cutaneous adverse drug reactions pose diagnostic and therapeutic challenges to the medical community. Understanding the pathomechanisms can prevent their onset and improve their management, while [...]

In the decade since their discovery, the two major breast cancer susceptibility genes BRCA1 and BRCA2, have been shown conclusively to be involved in a significant fraction of families segregating breast and ovarian cancer. However, it has become equally clear that a large proportion of families segregating breast cancer alone are not caused by mutations in BRCA1 or BRCA2. Unfortunately, despite intensive effort, the identification of additional breast cancer predisposition genes has so far been unsuccessful, presumably because of genetic heterogeneity, low penetrance, or recessive/polygenic mechanisms. These non-BRCA 1/2 breast cancer families (termed BRCAx families) comprise a histopathologically heterogeneous group, further supporting their origin from multiple genetic events. Accordingly, the identification of a method to successfully subdivide BRCAx families into recognizable groups could be of considerable value to further genetic analysis. We have previously shown that global gene expression analysis can identify unique and distinct expression profiles in breast tumors from BRCA1 and BRCA2 mutation carriers. Here we show that gene expression profiling can discover novel classes among BRCAx tumors, and differentiate them from BRCA1 and BRCA2 tumors. Moreover, microarray-based comparative genomic hybridization (CGH) to cDNA arrays revealed specific somatic genetic alterations within the BRCAx subgroups. These findings illustrate that, when gene expression-based classifications are used, BRCAx families can be grouped into homogeneous subsets, thereby potentially increasing the power of conventional genetic analysis.

Vitamin [B.sub.12] (cobalamin) is an essential cofactor of two enzymes, methionine synthase and methyimalonyl-CoA mutase. The conversion of the vitamin to its coenzymes requires a series of biochemical modifications for which several genetic diseases are known, comprising eight complementation groups (cblA through cblH). The objective of this study was to clone the gene responsible for the cblA complementation group thought to represent a mitochondrial cobalamin reductase. Examination of bacterial operons containing genes in close proximity to the gene for methylmalonyl-CoA mutase and searching for orthologous sequences in the human genome yielded potential candidates. A candidate gene was evaluated for deleterious mutations in cblA patient cell lines, which revealed a 4-bp deletion in three cell lines, as well as an 8-bp insertion and point mutations causing a stop codon and an amino acid substitution. These data confirm that the identified gene, MMAA, corresponds to the cblA complementation group. It is located on chromosome 4q31.1-2 and encodes a predicted protein of 418 aa. A Northern blot revealed RNA species of 1.4, 2.6, and 5.5 kb predominating in liver and skeletal muscle. The deduced amino acid sequence reveals a domain structure, which belongs to the AAA ATPase superfamily that encompasses a wide variety of proteins including ATP-binding cassette transporter accessory proteins that bind ATP and GTP. We speculate that we have identified a component of a transporter or an accessory protein that is involved in the translocation of vitamin [B.sub.12] into mitochondria.

Missense mutations in Cu,Zn-superoxide dismutase (SOD1) account for [approximately equal to] 20% of familial amyotrophic lateral sclerosis (FALS) through some, as yet undefined, toxic gain of function that leads to gradual death of motor neurons. Mitochondrial swelling and vacuolization are early signs of incipient motor neuron death in FALS. We previously reported that SOD1 exists in the intermembrane space of mitochondria. Herein, we demonstrate that the entry of SOD1 into mitochondria depends on demetallation and that heat shock proteins (Hsp70, Hsp27, or Hsp25) block the uptake of the FALS-associated mutant SOD1 (G37R, G41D, or G93A), while having no effect on wild-type SOD1. The binding of mutant SOD1 to Hsps in the extract of neuroblastoma cells leads to formation of sedimentable aggregates. Many antiapoptotic effects of Hsps have been reported. We now propose that this binding of Hsps to mutant forms of a protein abundant in motor neurons, such as SOD1, makes Hsps unavailable for their antiapoptotic functions and leads ultimately to motor neuron death. It also appears that the Hsp-SOD1 complex recruits other proteins present in the neuroblastoma cell and presumably in motor neurons to form sedimentable aggregates.

Abstract Clustering of cancer in families may be due to chance, inherited genetic mutations, common exposure to environmental agents, or a combination of these factors. The authors, to address a [...]

Byline: S. Ozen (1), Dilek Ertoy (2), Laurence Heidet (3), Loal Cohen-Solal (3), Haluk Ozen (4), Nesrin Besbas (1), Aysin Bakkaoglu (1), Corinne Antignac (3) Keywords: Keywords Familial benign hematuria; Phenotype; COL4A4 Abstract: We describe a father and three offspring with hematuria. The father and one girl also complained of flank pain. Renal function tests and ophthalmological examinations were normal in all. The father had very mild neural deafness. The renal biopsy samples of two affected siblings showed changes compatible with thin basement membrane disease. Genetic analysis revealed a novel missense mutation in exon 32 of COL4A4 to be responsible for the phenotype in this family. We suggest that thin basement membrane disease may have overlapping clinical features with other causes of hematuria genetic analysis may help in the differential diagnosis and help us further understand the disease processes. Author Affiliation: (1) Department of Pediatric Nephrology and Rheumatology, Hacettepe University Faculty of Medicine, 06100 Ankara, Turkey. sozen@gen.hun.edu.tr, TR (2) Department of Pathology, Hacettepe University Faculty of Medicine, 06100 Ankara, Turkey, TR (3) INSERM U423, University Rene Descartes, Ho^pital Necker-Enfants Malades, Paris, France, FR (4) Department of Urology, Hacettepe University Faculty of Medicine, 06100 Ankara, Turkey, TR Article note: Received: 29 January 2001 / Revised: 5 June 2001 / Accepted: 6 June 2001

Byline: J. Rodriguez-Soriano (1), Alfredo Vallo (2), Maria Jesus Quintela (2), Guiomar Perez de Nanclares (3), Jose Ramon Bilbao (3), Luis Castano (3) Keywords: Keywords Hypercalcemia; Hypercalciuria; Infancy; Calcium-sensing receptor Abstract: A 6-year-old boy presented with persistent hypercalcemia, hypercalciuria and nephrocalcinosis from early infancy. His 40-year-old father also had hypercalcemia and hypercalciuria. In both individuals serum values of intact parathyroid hormone (PTH) were repeatedly normal. Although these findings suggest a functional abnormality of the calcium-sensing receptor (CaR), no mutations in coding regions of the CaR gene could be demonstrated. Author Affiliation: (1) Department of Pediatrics, Hospital de Cruces, Plaza de Cruces s/n, Baracaldo, 48903 Vizcaya, Spain. jrs00014@teleline.es, ES (2) Department of Pediatrics, Hospital de Cruces and Basque University School of Medicine, Bilbao, Pais Vasco, Spain, ES (3) Division of Pediatric Nephrology and Research Unit, Hospital de Cruces and Basque University School of Medicine, Bilbao, Pais Vasco, Spain, ES Article note: Received: 2 January 2001 / Revised: 2 May 2001 / Accepted: 2 May 2001

Nine different gene mutations are responsible for causing familial hemiplegic migraine, which could account for the variety of symptoms. This type of migraine has a clear hereditary basis and usually causes some form of reversible paralysis during attacks.

This article discusses the genetic aspects of schizophrenia and identifies them as risk factors. Topics include family disease, molecular genetics, and chromosome deletion.

Blocking Gibbs sampling for linkage analysis in many-looped large pedigrees is discussed. This kind of sampling combines exact local computations with Gibbs sampling to complement strengths of both, and the method can handle problems of great complexity. No other known method can handle large pedigrees with many loops in linkage analysis. This sampling method, which operates on general Bayesian networks, is applied to a 73-person linkage problem related to the long QT syndrome (LQT), a rare heart disease.

The mucolipidosis type IV (MLIV) gene has been mapped to chromosome 19p using linkage analysis with 15 markers in 13 families, and this fact, with definition of founder haplotypes, is discussed. MLIV is a rare autosomal recessive disease and a lysosomal storage disorder involving severe neurologic and ophthalmologic abnormalities. The majority of those diagnosed with it so far are of Ashkenazi Jewish descent and genetic prenatal diagnosis will now be possible in affected families.

A second gene has been found for autosomal dominant Mobius syndrome in a Dutch family other than the one previously studied, and genetic heterogeneity has been established. Familial recurrence may be seen, but cases are most often sporadic. The gene has been localized to chromosome 10q using linkage analysis in a large Dutch family with autosomal dominant inherited facial paresis. Different pedigrees have suggested different modes of inheritance.

Benign adult familial myoclonic epilepsy (BAFME), an autosomal dominant idiopathic epileptic syndrome recently recognized in Japanese families, is discussed relative to its localization to chromosome 8q23.3-q24.1. The gene locus was assigned by linkage analysis in a large Japanese kindred.

Leukoencephalopathy with vanishing white matter (VWM), an autosomal recessive disorder with normal early development and childhood-onset neurological deterioration in most cases, is discussed with the information that the gene that is located on chromosome 3q27. It had appeared from genealogical studies that seven parents in four Dutch families with VWM may have inherited a disease allele from a common ancestor at least eight generations back. A genome linkage screening has been carried out for 19 families of varying ethnic origins.

Recent genetic studies of substance abuse and alcoholism are reviewed with emphasis on alcoholism and related phenotypes. Such studies have been carried out in large numbers in the year just past, the result of high repeated-heritability estimates of the addictive disorders and related phenotypes and of realization that methods of mapping, detecting and characterizing oligogenic susceptibility genes are improving rapidly.

A major quantitative-trait locus for mole density linked to the familial melanoma gene CDKN2A (ital) is discussed with information about a maximum-likelihood combined linkage and association analysis in twins and their siblings. Raised and flat nevi appear to have very differnt etiologies based on the findings of the study with total heritability higher for raised than for flat moles.

Linkage of familial combined hyperlipidemia (FCHL), a common lipid familial lipid disorder, with a locus on chromosome 11 is discussed, as is the genome scan for it. It appears that FCHL, which is present in 10-20% of those with premature coronary heart disease, is complex and heterogeneous.

Byline: H. I. Cheong (1), Jong Hee Chae (1), Jung Sue Kim (1), Hye Won Park (2), Il Soo Ha (1), Yong Seung Hwang (1), Hyun Soon Lee (3), Yong Choi (1) Keywords: Key wordsaMELAS syndrome; Alport syndrome; Focal segmental glomerulosclerosis; Hearing loss; Diabetes Abstract: Several cases of hereditary glomerulopathy associated with an A to G transition at position 3243 in mitochondrial DNA, which is known to be associated with most cases of MELAS syndrome (myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), have been recently reported. These patients share the characteristics of hereditary progressive glomerular disease and hearing loss with Alport syndrome. We therefore screened 27 patients with kidney disease clinically mimicking Alport syndrome for the presence of the 3243 mitochondrial mutation, and found one girl with the mutation and a positive family history. Her clinical features were very similar to those of all cases reported to date. An absence of hematuria, severe kidney involvement in a female, pathological changes of focal segmental glomerulosclerosis with no basket-weave change of the glomerular capillary wall, and the frequent association of steroid-induced diabetes are the major features that distinguish this condition from Alport syndrome. Careful neurological examination may detect neuromuscular symptoms compatible with mitochondrial cytopathies. In conclusion, progressive glomerulopathy should be included in the broad spectrum of mitochondrial cytopathies, especially in cases of MELAS syndrome. This mutation should also be included in the etiologies of secondary focal segmental glomerulosclerosis and in the differential diagnosis of Alport syndrome. Author Affiliation: (1) Department of Pediatrics, Seoul National University Children's Hospital, 28 Yongon-Dong, Chongro-Gu, Seoul 110-744, Korea e-mail: cheonghi@plaza.snu.ac.kr Tel.: +82-2-760-2810, Fax: +82-2-743-3455, KR (2) Department of Pediatrics, Seoul City Boramae Hospital, Seoul, Korea, KR (3) Department of Pathology, Seoul National University Hospital, Seoul, Korea, KR Article note: Received: 16 June 1998 / Revised: 16 October 1998 / Accepted: 17 October 1998

Byline: M. Bosio (1), Maria Luisa Bianchi (2), Sarah E. Lloyd (3), Rajesh V. Thakker (3) Keywords: Key wordsaRenal phosphate leak; Microglobulinuria; Hypercalciuria; Nephrocalcinosis; Chloride channel gene; Osteopenia; Renal familial syndrome Abstract: aWe describe a familial syndrome in two brothers who were investigated after the casual discovery of tubular proteinuria in their 1st month of life. During a follow-up of 20 and 11 years, respectively, the two children grew well and were asymptomatic, but developed the same biochemical abnormalities, i.e., tubular proteinuria and hyperphosphaturia, progressive decrease in serum phosphorus below the normal values for age, and an increase in serum 1,25-dihydroxyvitamin D levels over normal values. Moreover, hyperabsorptive hypercalciuria and systemic osteopenia developed and progressively worsened. In both children, at a different age, medullary nephrocalcinosis appeared. The oldest boy suffered a progressive decrease in urinary concentration ability and in glomerular filtration rate. Oral phosphate supplementation led to reversal of all biochemical abnormalities, with the exception of decreased phosphate tubular reabsorption and tubular proteinuria. With long-term phosphate supplementation, a normal bone mass was reached, while progression of nephrocalcinosis was arrested and impairment of renal function was slowed down. In a family study (siblings and parents), the only detectable abnormality was microglobinuria in the mother, thus suggesting a X-linked inheritance of this disorder. In the two probands a mutation within the renal chloride channel gene (CLCN5) was discovered. Author Affiliation: (1) Pediatric Nephrology Section, Department of Pediatrics, Magenta Hospital, Via Donatore de Sangue 50, I-20013 Magenta (MI), Italy Tel.: +390-2-97963317, Fax: +390-2-97963235, IT (2) Bone Metabolic Unit, Istituto Auxologico Italiano IRCCS, Via L. Ariosto 13, I-20155 Milano, Italy, IT (3) MRC Molecular Endocrinology Group, MRC Clinical Science Center, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12, UK, GB Article note: Received: 23 December 1997 / Revised: 7 July 1998 / Accepted: 7 July 1998

A familial moyamoya disease gene has been mapped to chromosome 3p13.1-p26, the first genetic locus found for the disease. The disease, which is prevalent in patients younger than 10, in most cases is apparently sporadic, but about 10% of cases are familial. A genomewide search was carried out in 16 families. Spontaneous occlusion of the circle of Willis or moyamoya disease is characterized by occlusion of the terminal portion of the internal carotid artery and/or bilateral stenosis.

The molecular mechanism of Angelman syndrome (AS) has been studied in two large families with the finding that there is an imprinting mutation. In several patients in the past microdeletions upstream of the SNRPN (ital) gene have been seen, defining an imprinting center (IC) hypothesized to regulate the imprint switch process in the male and female germlines. In the families an AS imprinting mutation was segregated. One of the families was described in an earlier genetic linkage of AS to 15q11-q13. The original linkage is for the 15q11-q13 IC. Affected patients in the AS families have either a 5.5- or a 15-kb microdeletion, one of which narrowed the shortest region of deletion overlap to 1.15 kb in all the cases. The small region defines a component of the IC involved in AS, the paternal-to-maternal switch element. Genetic counseling issues for AS and Prader-Willi syndrome are brought out by the research.

Fragile sites involve both cytogenetic similarity and molecular diversity. Some common fragile sites may affect gene expression, setting up local regions of instability. Understanding mechanisms of the instability and the biological significance is a challenge. Just three of the various classes of rare fragile sites have been studied from the molecular perspective and more is known about the folate-sensitive ones than others. Fragile sites are classified with some cytogenetic and molecular properties.

Familial benign hypercalcemia, Oklahoma variant (FBH(sub.Ok)), has been linked to eight chromosome-19q13 loci. This will be helpful to the identification process for another calcium-sensing receptor (CaSR) or a mediator of calcium homeostasis. A genomewide search was performed using chromosome-specific sets of microsatellite polymorphisms in an Oklahoma family with an FBH variant (FBH (sub.Ok)), for which linkage to 3q and 19p had been excluded. Inactivating CaSR mutations brings familial benign hypercalcemia (FBH) or familial hypocalciuric hypercalcemia (FHH). Activated mutations bring on hypocalcemic hypercalciuria. Additional CaSRs or second messengers are implicated. Calcium homeostasis regulated by the parathyroids and kidneys is mediated by the CaSR. It is located on 3q21-q24 and is part of the superfamily of G-protein coupled receptors.

A gene for familial hemophagocytic lymphohistiocytosis (FHL), familial histiocytic reticulosis, and familial erythrophagocytic lymphohistiocytosis, has been localized at chromosome 9q21.3-22 using homozygosity mapping in four inbred families of Pakistani descent. The combined maximum multipoint LOD score was 6.05. Homozygosity across the interval could not be found in another affected kindred, one of Arab origin with a maximum multipoint LOD score of -0.12. Identification of the genes will be helpful to the effort to understand control of macrophage and T-lymphocyte activation. FHL is a rare early-childhood autosomal recessive disorder and involves excessive immune activation.

Familial calcium pyrophosphate dihydrate deposition disease (CPPDD) has been documented in a French kindred from the Alsace region and in an Argentinean kindred of northern Italian ancestry. Family members who were affected were karyotypically normal. Linkage was found to the short arm of chromosome 5. In the Argentinean group, recombinants made it possible to designate a region less than 1 cM in length between D5S416 and D5S2114 as the CPPDD locus.

An extension of one of three recently developed family-based tests of association and linkage using unaffected siblings as surrogates for untyped parents is proposed. The four tests are then compared using as an example the application to a complex disease for both biallelic and multiallelic markers and for sibships of varying sizes, then looking at availability of some parental data.

Pallido-ponto-nigral degeneration (PPND) is one of the most well characterized familial neurodegenerative disorders linked to chromosome 17q21-22. These hereditary disorders are known collectively as frontotemporal dementia (FTD) and parkinsonism linked to chromosome 17 (FTDP-17). Although the clinical features and associated regional variations in the neuronal loss observed in different FTDP-17 kindreds are diverse, the diagnostic lesions of FTDP-17 brains are tau-rich filaments in the cytoplasm of specific subpopulations of neurons and glial cells. The microtubule associated protein (tau) gene is located on chromosome 17q21-22. For these reasons, we investigated the possibility that PPND and other FTDP-17 syndromes might be caused by mutations in the tau gene. Two missense mutations in exon 10 of the tau gene that segregate with disease, Asn[279.sup.Lys] in the PPND kindred and Pro[301.sup.Leu] in four other FTDP-17 kindreds, were found. A third mutation was found in the intron adjacent to the 3[prime] splice site of exon 10 in patients from another FTDP-17 family. Transcripts that contain exon 10 encode tau isoforms with four microtubule (MT)-binding repeats (4Rtau) as opposed to tau isoforms with three MT-binding repeats (3Rtau). The insoluble tau aggregates isolated from brains of patients with each mutation were analyzed by immunoblotting using tau-specific antibodies. For each of three mutations, abnormal tau with an apparent [M.sub.r] of 64 and 69 was observed. The dephosphorylated material comigrated with tau isoforms containing exon 10 having four MT-binding repeats but not with 3Rtau. Thus, the brains of patients with both the missense mutations and the splice junction mutation contain aggregates of insoluble 4Rtau in filamentous inclusions, which may lead to neurodegeneration.

Byline: Melly Ohali (1), Hanna Shalev (2), Menachem Schlesinger (3), Yitzhak Katz (4), Leonid Kachko (5), Rivka Carmi (6), Shaul Sofer (2), Daniel Landau (2) Keywords: Key words: Hemolytic uremic syndrome; Familial; Complement components; Thrombotic microangiopathy Abstract: We describe the clinical course, complement components, and pathological findings of 10 infants with autosomal recessive hemolytic uremic syndrome (HUS). All patients were members of one extended highly inbred Bedouin kindred. The median age of presentation was 2 weeks (range 1--20 weeks). Eight patients died, 2 patients are alive, on dialysis. Renal biopsies revealed thrombotic microangiopathy with a predominant early arteriolar involvement and subsequent development of ischemic glomerular changes. Immunofluorescence was positive for C3 in glomeruli. All patients had low complement components levels during and between relapses, and in some this was evident soon after birth and prior to the onset of symptoms. This deficiency could not be normalized by repeated plasma transfusions. Biosynthetic labelling of patients' fibroblasts demonstrated normal rates of C3 protein synthesis. Serum factor H levels were greatly decreased or absent in 4 patients tested and moderately decreased in 15 of 23 healthy unaffected siblings and patients. This defect may cause complement activation and consumption, possibly at the endothelial cell level. Author Affiliation: (1) Department of Pediatrics, Barzilai Medical Center, Ashkelon, Israel, IL (2) Department of Pediatrics, Soroka Medical Center, Beer Sheva, Israel, IL (3) Immunology Unit, Barzilai Medical Center, Ashkelon, Israel, IL (4) Allergy and Immunology Unit, Asaf Harofeh Hospital, Zrifin, Tel Aviv University Sackler School of Medicine, Tel Aviv, Israel, IL (5) Department of Pathology, Soroka Medical Center, Beer Sheva, Israel, IL (6) Department of Genetics, Soroka Medical Center, Beer Sheva, Israel, IL Article note: Received April 18,1997 received in revised form and accepted January 27, 1998

Jumping genes were originally thought to exist only in plants and bacteria, but they also may play a role in human disease. Barbara McClintock won the Nobel prize in 1983 for discovering that genes are not permanently fixed on chromosomes, but can and do move around. Genes are often recombined during meiosis, the process by which the male and female sex cells are formed. However, transposition of genes can also occur in somatic, or body, cells. Some jumping genes called transposons insert themselves into DNA in much the same way some viruses do. When this happens, the disruption of the existing gene can cause the expression of altered proteins that can cause disease. Hemophilia A, familial hypercholesterolemia and retinitis pigmentosa are examples of diseases that may be caused by jumping genes. Certain cancers are caused by an exchange of material between two chromosomes, which can also disrupt the normal function of the existing genes.

Hereditary hearing loss that begins early in life may be traced to a gene on chromosome 1p. Researchers studied a large Indonesian family with hereditary, progressive deafness. DNA samples were analyzed from 15 family members with hearing loss. A genetic-linkage analysis was performed to pinpoint the location of the gene for deafness. The gene was localized between D1S211 and D1S201 on chromosome 1p. Linkage analysis was then performed in American and Dutch families with hereditary hearing loss to determine if the same region on chromosome 1p was the location of the gene for deafness. In the American family, the gene was positioned on D1S255 on chromosome 1p. In the Dutch family, the gene for deafness was not located in the suspected region on chromosome 1p. Because the Indonesian and American families are of different ethnic groups, researchers suspect that the gene that causes deafness on chromosome 1p may be responsible for hereditary hearing loss in other families.

Resistance to the anticoagulant activated protein C (APC) appears to be inherited and associated with familial thrombosis. Protein C is important in the prevention of blood clots. Thrombosis is the formation of blood clots. A total of 104 patients with thrombosis were compared with 130 patients without (comparison group). Additionally, 211 family members of 34 patients with thrombosis and resistance to APC were evaluated. APC resistance ratios of less than 2.0, calculated using a modified blood clotting measure, were associated with thrombosis. Approximately 45% of family members of patients had a ratio of less than 2.0. Forty percent of patients with thrombosis had ratios below 2.0. However, 50% of patients with a family history of thrombosis had ratios below 2.0. In the comparison group, only 7% had ratios below 2.0. Those with APC resistance appear at an increased risk of thrombosis.

Women with a family history of breast cancer may have a higher risk of developing the disease themselves. This risk still may exist even if the closest family member with the disease is a third-degree relative such as cousins. Researchers examined the Mormon genealogical information from the Utah Population Database and data from the Utah Cancer Registry and the Utah Department of Vital Statistics to determine the family history risk of breast cancer. The risk of breast cancer was three times higher for individuals with the highest family history score than for those with the lowest family history score. The risk of breast cancer was approximately twice as high if the family member with breast cancer was a first-degree relative, a mother or sister, rather than a third-degree relative. Women whose mother had breast cancer had a higher risk than those whose sister had the disorder., Objective. - The purpose of this study is to assess the impact of family history on the fisk of developing breast cancer. Design. - A case-control study design was used. Setting. - To provide a comprehensive assessment of family history risk, we used the Utah Population Database, a linked database compiled of genealogy data of the descendants of Mormon pioneer families, cancer data from the Utah Cancer Registry, and mortality data from the Utah Department of Vital Statistics. Patients. - All women diagnosed with breast cancer who were in the genealogy database and the Utah Cancer Registry were included. Controls were women selected from the genealogy, who like cases had no record of previous cancer. They were matched to the cases by age and place of birth. Outcome. - Several definitions of family history were used. The total familial fisk variable, developed to work effectively in the Utah Genealogy Database, accounts for all family members, their degree of relatedness to the case, and the amount of time they were observed for possible cancer diagnosis. Results. - A threefold increase in risk, estimated by the odds ratio (OR), of breast cancer among those with the highest family history score (6% of cases) was observed when compared with those with the lowest family history score. The OR for women with a first-degree relative with breast cancer was 2.45 (95% confidence interval [CI], 1.84 to 3.06). If the nearest relative was a second-degree relative, the OR was 1.82 (95% CI, 1.39 to 2.24); if the nearest relative was a third-degree relative, the OR was 1.35 (95% CI, 1.07 to 1.64). A slightly greater risk was observed if the first-degree relative was a woman's mother (OR, 2.44; 95% CI, 1.77 to 3.42) rather than a sister (OR, 2.01; 95% CI, 1.66 to 2.43). Among subjects diagnosed before the age of 50 years, the disease experience of relatives prior to age 50 was most important, while for older subjects the experience of relatives of all ages was of roughly equal importance. Women who developed contralateral breast cancer within 3 years of initial diagnosis were nearly 10 times as likely as women without breast cancer to have a first-degree relative with breast cancer. Based on the fisk estimates in this study, we have estimated that approximately 17% to 19% of breast cancer in the population could be attributed to family history. Women who had a first-degree relative with colon cancer had a 30% increased risk of breast cancer. Conclusions. - In this study population, women with a family history of breast cancer, even if the nearest relative with breast cancer is a third-degree relative, are at increased risk of the disease. (JAMA. 1993;270:1563-1568)

Mutations in the gene for glucokinase may be one of the causes of maturity-onset diabetes of the young, a type of adult-onset diabetes that occurs in young people. Glucokinase is an enzyme in the pancreas and liver that is involved in glucose metabolism. A study examined genetic mutations in glucokinase among individuals from 32 families with maturity-onset diabetes of the young and 21 families with adult-onset diabetes. DNA analysis revealed that over half the families with maturity-onset diabetes of the young had mutations in the glucokinase gene. Sixteen different mutations were found among individuals from 18 of these families No mutations in the gene for glucokinase were found among the individuals with late-onset diabetes. Patients with maturity-onset diabetes of the young whose families carried a gene defect usually began suffering from mild hyperglycemia in childhood, but those without these mutations were more likely to develop hyperglycemia after puberty.

Two case studies of reverse mutations in families with myotonic dystrophy are presented. Myotonic dystrophy is a hereditary, multisystem disorder characterized by muscle weakness, wasting, cataracts and heart disturbances. The gene mutation responsible for myotonic dystrophy has recently been identified. In Family 1, the fetus of a healthy mother and a father with myotonic dystrophy had inherited the mutation from her father. However, upon further DNA analysis, the abnormal chromosome in the fetus appeared to have undergone a complete, spontaneous correction of the mutation. A healthy baby girl was born. In Family 2, an asymptomatic 25-year-old man had inherited the mutation from his father. Again, the affected gene had reverted. Reverse mutation has not previously been observed in humans, but has been reported in studies of bacteria and laboratory cultures of mammalian cells. The instability of the abnormal gene may explain the reversion.