Anticipation (genetics)

About: Anticipation (genetics) is a research topic. Over the lifetime, 669 publications have been published within this topic receiving 21784 citations. The topic is also known as: Genetic Anticipation & Anticipation, Genetic.

Primary cataract as a key to recognition of myotonic dystrophy type 1.

Abstract: PURPOSE: Primary cataract is often the initial manifestation of the adult-onset type of myotonic dystrophy type 1 (DM1), the most common muscular dystrophy in adults. It is caused by a CTG repeat expansion within the DMPK gene, and anticipation may cause earlier onset and more severe symptoms in subsequent generations. METHODS: We report a family with hereditary cataract, which was initially classified as primary hereditary cataract. After presentation of 2 children with motor development delay and behavioral changes, DM1 was diagnosed. Subsequently, various DM1 features were recognized in older family members. CONCLUSIONS: This report aims to increase awareness among ophthalmologists of the high prevalence of DM1 among young primary cataract patients. Ophthalmologists can play a significant role in early diagnosis, since cataract frequently is the first occasion that patients seek medical attention. Early recognition is crucial since it enables adequate cardiac follow-up and allows counseling of couples of childbearing age.

New data on the genetic profile and penetrance of hereditary Val30Met transthyretin amyloidosis in Sweden.

Abstract: INTRODUCTION Hereditary transthyretin (ATTRv) amyloidosis is of autosomal dominant transmission, caused by a spectrum of mutations in the transthyretin (TTR) gene. The ATTRV30M (p.Val50Met) is the most frequent substitution in Europe. Northern Sweden is a known cluster for ATTRV30M amyloidosis patients due to high prevalence of the mutation rate, with homozygous cases. First symptoms occur generally during the 6th decade. Previous studies reported low penetrance in this area and possible anticipation in families. In order to refine our knowledge of the genetic aspects, penetrance and factors that influence the disease's risk, we performed a comprehensive study of ATTRV30M families in Sweden. METHODS To assess anticipation, well-established age at onset (AO) was compared in all informative parent-offspring pairs and in subgroups, after excluding ascertainment biases. Penetrance was estimated using a non-parametric method that enables to study covariates' effect on the disease's risk. RESULTS We analysed 114 ATTRV30M Swedish families, including 12 homozygous individuals. Among 131 parent-offspring pairs, we found an average anticipation of 11.7 [Standard Deviation (SD) =10.03] years, higher in case of maternal transmission (mean ± SD = 13.7 ± 8.4 years), compared to paternal transmission (mean ± SD = 7.9 ± 11.5 years, p < .003). Anticipation remained significant, after exclusion of ascertainment biases. In heterozygous ATTRV30M kindred, penetrance was low, estimated below 10% [95% confidence interval (CI) = 6-10] at 40 years-old, increasing to 71% [95% CI= 65-76] at age 90 years. The risk was found to be higher in male patients (p < .01) and in case of maternal transmission (p < .01), reflecting a parent of origin effect. We observed no difference of penetrance according the geographical origin. Finally, the disease risk was similar in heterozygous and homozygous ATTRV30M amyloidosis individuals. CONCLUSIONS Our study provides new data on the genetics of ATTRV30M families in Sweden, including the occurrence of anticipation and on penetrance. Both are increased in case of maternal inheritance and in male patients. Overall, gender seems to be a factor that substantially modulates the AO of the disease, in this area. Clinically, these findings are of importance to guide the management of sibships and the monitoring of mutation carriers.

Whole-exome analysis of a Li-Fraumeni family trio with a novel TP53 PRD mutation and anticipation profile.

Abstract: Li-Fraumeni syndrome is a clinically heterogeneous familial cancer predisposition syndrome with autosomal-dominant inheritance caused by heterozygous germline mutations in the TP53 gene. We here analyze the genetic background of a family with a 4-year-proband presented with a Li-Fraumeni tumor. The mother developed breast cancer at age 37 and the proband died at age 8. We performed Sanger sequencing and whole-exome sequencing on peripheral blood DNA from proband and relatives. Data analysis selected only high-quality score and depth reads, rare variants and protein impact involving missense, non-sense, frameshift and splice disrupt mutations. Disease implicated variants and predicted deleterious alterations were also chosen. TP53 genetic testing revealed a never reported TP53 deletion arose as de novo mutation in the mother and inherited by the proband. We then performed whole-exome analysis of the trio to uncover inherited variants from the father that potentially worsen the already altered genetic background in the proband. No pathogenic variants were inherited in autosomal recessive, de novo dominant or X-linked recessive manner. Comparing proband and father exome we detected 25 predicted deleterious variants including a nonsense mutation in ERCC3. Those inherited mutations are possible candidate modifiers linked to TP53, explaining the proband accelerated tumor onset compared to the mother and providing a possible explanation of the genetic anticipation event in this Li-Fraumeni family.

Instability of CAG-trinucleotide repeats in chronic lymphocytic leukemia.

Abstract: Anticipation--earlier onset and more severe disease in the offspring generation--is a well documented feature of familial chronic lymphocytic leukaemia (CLL). In a number of Mendelian diseases, anticipation is caused by expansion of contiguous triplets of nucleotides. The severity of disease expression and penetrance is related to the extent of the triplet expansion. To investigate whether repeat nucleotide repeat expansion is a feature of CLL, the repeat expansion detection (RED) technique was applied to samples from 17 patients with familial disease and 32 patients with early-onset CLL disease. No potentially pathological CAG expansions were detected. We conclude that unstable CAG repeat expansion is not a feature of CLL and that other processes are likely to be involved in generating anticipation in familial forms of the disease.