Individuals In Kindred Research Articles

Risk of Pancreatic Cancer in the Long-Term Prospective Follow-Up of Familial Pancreatic Cancer Kindreds.

A family history of pancreatic cancer is associated with increased pancreatic cancer risk. However, risk estimates for individuals in kindreds with an aggregation of pancreatic cancer (>1 relative) are imprecise because of small samples sizes or potentially impacted by biases inherent in retrospective data. The objective of this study is to determine the age-specific pancreatic cancer risk as a function of family history using prospective data. We compared pancreatic cancer incidence (n = 167) in 21 141 individuals from 4433 families enrolled in the National Familial Pancreatic Cancer Registry with that expected based on Surveillance Epidemiology and End Results data and estimated the cumulative probability of pancreatic cancer using competing risk regression. Familial pancreatic kindred members (kindreds with pancreatic cancer in 2 first-degree relatives [FDRs] or a pathogenic variant) had a standardized incidence ratio of 4.86 (95% confidence interval [CI] = 4.01 to 5.90), and sporadic kindred members (kindreds not meeting familial criteria) had a standardized incidence ratio of 2.55 (95% CI = 1.95 to 3.34). Risk in familial pancreatic cancer kindreds increased with an increasing number of FDRs with pancreatic cancer, with a standardized incidence ratio of 3.46 (95% CI = 2.52 to 4.76), 5.44 (95% CI = 4.07 to 7.26), and 10.78 (95% CI = 6.87 to 16.89) for 1, 2, and 3 or more FDRs with pancreatic cancer, respectively. Risk was also higher among individuals with a family history of young-onset (aged younger than 50 years) pancreatic cancer. Pancreatic cancer risk is strongly dependent on family history, including both the degree of relationship(s) and age of onset of pancreatic cancer in relatives. These risk estimates will help inform the design of early detection studies and the risk and benefit analysis of screening trials.

Neuropsychiatric abnormalities in familial frontotemporal dementia: Findings from the LEFFTDS Cohort

AbstractBackgroundThe LEFFTDS Consortium involves investigators at 8 centers in North America evaluating individuals in kindreds with mutations in microtubule associated protein tau (MAPT), progranulin (GRN), or chromosome 9 open reading frame 72 (C9orf72) genes using a standardized battery of measures. Participants are evaluated annually. We sought to determine possible correlations between FTLD disease progression and neuropsychiatric features.MethodThe Neuropsychiatric Inventory Questionnaire (NPI‐Q) scale is an informant‐based instrument that measures the presence and severity of 12 neuropsychiatric features in patients with dementia. The NPI‐Q was completed at each LEFFTDS visit. The individual NPI questions and total score were analyzed in those with CDR® Dementia Staging Instrument PLUS National Alzheimer Coordinating Center Frontotemporal Lobar Degeneration (CDR®+ NACC FTLD) ratings of 0 (i.e., clinically normal), 0.5 (i.e., questionably/minimally abnormal), 1, 2, and 3.ResultThe 472 participants enrolled to date with a baseline (Visit 1) assessment have the following characteristics: 261 (55.5%) female, mean age 48 (range 18‐80) years, mean education 16 (range 11‐22) years, and 275 participants with a CDR®+NACC FTLD=0 (58%) and known genetic status. Participants with a CDR®+NACC FTLD=0 plus a genetic mutation were compared to those without a mutation and found to have increased severity of apathy (mean score of 0.116 versus 0.035, p=0.0302). Regardless of the specific mutation, those with a CDR®+NACC FTLD=0.5 were reported to have increased severity of apathy, disinhibition, and irritability. For most domains, mean NPI‐Q severity scores increase between groups up to CDR®+NACC FTLD=2. Depression increases in severity up to CDR®+NACC FTLD=1, whereas apathy severity continues to increase with increasing disease severity through CDR®+NACC FTLD=3. Twenty participants converted from CDR®+NACC FTLD 0 to >0 between their baseline and most recent visit; apathy severity almost tripled in these participants. For those that converted, disinhibition, irritability, and NPI total score were different between baseline and most recent visit (Wilcoxon signed rank test, p<0.05).ConclusionKey neuropsychiatric features measured by the NPI‐Q demonstrate differences in apathy severity between clinically normal mutation vs non‐mutation carriers. Key domains differ at different levels of FTLD severity and show dynamic changes with increasing level of FTLD severity. Supported by AG063911, AG045390, NS092089, AG016976.

Screening for genetic causes of hypertension.

Monogenic or single-gene forms of human hypertension result from mutations involving regulatory elements of the renin-angiotensin-aldosterone system (RAAS) or occur in syndromes associated with hereditary pheochromocytoma. RAAS gain-of-function mutations result in sodium retention, suppression of plasma renin activity, and often, but not invariably, hypokalemia. Hereditary RAAS syndromes result from intrinsic renal abnormalities (apparent mineralocorticoid excess and Liddle's syndromes) or from mineralocorticoid excess states (congenital adrenal hyperplasia and glucocorticoid-remediable aldosteronism). In the hereditary pheochromocytoma syndromes many asymptomatic individuals are identified because they are at-risk individuals in kindreds with a pheochromocytoma-predisposing syndrome. On the other hand, up to 25% of subjects with presumed "sporadic" pheochromocytoma have germline mutations in one of four pheochromocytoma susceptibility genes (the RET proto-oncogene, von Hippel-Lindau gene, neurofibromatosis F1 gene, and succinate dehydrogenase subunit D and succinate dehydrogenase subunit B genes). Hereditary pheochromocytomas are typically intra-adrenal and bilateral and patients typically present at younger ages compared with sporadic pheochromocytoma.

Inheritance of diseases primary in the muscles

1. 1. Hereditary muscular diseases can best be studied in large family groups in which the variety of expressions of the same gene can be identified. Extending examinations by physicians to greater numbers of individuals in kindreds being studied will also add much to our understanding of these diseases and our knowledge of the pattern of their inheritance. 2. 2. Progressive muscular dystrophy is perhaps the most important and best known group of muscular disorders. 3. 3. Most cases of progressive muscular dystrophy can be classified into two general groups, the facioscapulohumeral type and the childhood type. Each of these is inherited as a separate genetic entity following a different pattern of inheritance. 4. 4. Facioscapulohumeral progressive muscular dystrophy varies in its form of expression. Its age of onset is usually between seven and twenty years. It is inherited as an autosomal dominant. 5. 5. Childhood progressive muscular dystrophy differs from facioscapulohumeral muscular dystrophy both in its mode of inheritance and in its pattern of expression. The age of onset is usually about three years. There is good evidence that it is inherited as a sex-linked recessive trait. 6. 6. The gene producing childhood muscular dystrophy has a high mutation rate. Its minimum mutation rate is roughly estimated at one in 10,000 (approximately 1 × 10 −5). 7. 7. Three types of myotonia are discussed, myotonia congenita (Thomsen's Disease), paramyotonia and myotonia dystrophica. 8. 8. Myotonia congenita is not a common disease. It is congenital or can be identified at a very early age. It is inherited as an autosomal dominant. 9. 9. Paramyotonia is a rare disease. It is expressed as an immobility of the muscles brought on by cold. It can be detected when a child is but a few months old and is inherited as an autosomal dominant. 10. 10. Myotonia dystrophica is the most common as well as the most severe form of the myotonias. It is inherited as an autosomal dominant with a wide variability of expression. 11. 11. It is evident that all cases of family periodic paralysis described in the literature are not due to the same mutation. In the kindred studied at the University of Utah the defect was inherited as an autosomal dominant. 12. 12. Since the traits described as being due to autosomal dominant genes have not occurred in the homozygous condition it cannot be determined whether or not dominance is complete or what the expression of the homozygoteis T able II Statistical, Comparison of data on kindred with periodic paralysis with the theoretic behavior of a dominant trait ∗ Phenotypes Observed Calculated Deviation Standard Error D/SE Normal (pp) 36 34 2 4.12 485 Affected (Pp) 32 34 2 Total 68 68 ∗ From Tyler, Stephens, Gunn and Perkoff, J. Clin. Investigation, 1951.