Large normal and reduced penetrance alleles in Huntington disease: instability in families and frequency at the laboratory, at the clinic and in the population

Abstract

Large normal ('intermediate') alleles may produce de novo expansions in Huntington disease; nevertheless, there is very little evidence about their population prevalence and impact in daily practice, and there are conflicting reports about the extent of their instability. We estimated the frequency of large normal alleles (27-35 CAGs) and of reduced penetrance alleles (36-39 CAGs), as well as the frequency of genotypes carrying them, in (i) a diagnostic laboratory, (ii) a genetic counselling clinic and (iii) the general population. Large normal alleles were present in 6% of a large control sample, 7% of consultands who took pre-symptomatic testing and 7% of samples in the laboratory. Reduced penetrance alleles were found in 1 of 1772 control chromosomes (0.1% of individuals), 5% of 146 pre-symptomatic testees and over 2% of 1214 diagnostic samples (350 families). All 16 alleles sized 27-32 CAGs seemed to be transmitted stably; alleles ≥ 36 repeats were unstable in five families. Seven small full penetrance alleles contracted into the reduced penetrance range, but none into the large normal range. Evidence showed that large normal alleles are relatively frequent and that those with reduced penetrance are not a rare event, either at the laboratory or the clinic. This reinforces the need to understand the genomic context of repeat instability in each family and population.

REVIEW-ARTICLE Intermediate alleles of Huntington’s disease HTT gene in different populations worldwide: a systematic review

“…One European study analyzed prenatal tests (between 1998 and 2008) of couples with family history of HD and reported a frequency of 4% IA (van Rij et al, 2014). Another study examined 13 transmissions of intermediate and reduced penetrance alleles in 12 families from Portugal and showed only instability of transmission in 1/3 of the carriers who had reduced penetrance alleles (Sequeiros et al, 2010).…”

“…Large, normal, and reduced penetrance alleles in HD: instability in families and frequency at laboratory, clinic, and population (Sequeiros et al, 2010) Automated capillary electrophoresis Latin America 3.5% 3%…”

CAG size-specific risk estimates for intermediate allele repeat instability in Huntington disease

“…IAs have between 27 and 35 CAG repeats, a range that falls just below the disease-threshold of 36 repeats, although disease alleles with 36–39 CAG display reduced penetrance 3. IAs have been identified at a high frequency in the general population—approximately 6% of persons with no known association with HD have an IA, suggesting that upwards of 1 in 17 persons may receive an IA predictive test result 4 5…”

Genetic counseling and testing for Huntington's disease: A historical review

“…[1989] Discusses requests for predictive testing of affected individuals, minors, impact on relatives, use of research samples for clinical purposes Demyttenaere et al [1992] Discusses challenging counseling situations Harper and Newcombe [1992] Use of life table risk estimates in counseling; anticipates the report of Brinkman et al [1997] Heimler andZanko [1995], Reich et al [1996] Case report of testing monozygotic twins Mehlman et al [1996], Burgess et al [1997], Uhlmann et al [1996], Visintainer et al [2001] Anonymous testing Alford et al [1996] Challenging laboratory and clinical scenarios Almqvist et al [1997] Discusses the impact of the unusual situation of a reversal of risk between a linkage analysis and direct gene analysis Maat-Kievit et al [1999b], Benjamin and Lashwood [2000], Lindblad [2001] Testing individuals at 25% risk Alonso et al [2002], Squitieri et al [2003] Counseling about unexpected homozygosity for an expanded allele; predictive testing for patients at risk for homozygosity Nahhas et al [2009] Contraction of an abnormal allele into the reduced penetrance range Hendricks et al [2009] Estimating the probability of de novo HD in the children of male carriers of high-normal alleles Sequeiros et al [2010], Semaka et al [2013c] Frequency of intermediate and reduced penetrance alleles Chen et al [2012] Use of a novel model for estimating genetic risk incorporating family information Palomaki and Richards [2012] Laboratory proficiency testing Semaka et al [2013a] Patient comprehension of the implications of an intermediate allele Squitieri and Jankovic [2012], Ha et al [2012] Possibility of a phenotype associated with CAG repeat lengths of 27-35 Semaka et al [2013bSemaka et al [ , 2015, Semaka and Hayden (2014) CAG size-specific risk estimates for intermediate allele repeat instability; counseling implications; case report of expansion of a maternal intermediate allele Bean and Bayrak-Toydemir [20...…”