Molecular detection of new mutations, resolution of ambiguous results and complex genetic counseling issues in Huntington disease

Abstract

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by expansion of a variable length (CAG)n repeat in the 5' coding region of a novel gene on chromosome 4p16.3. We provide comprehensive molecular analysis of a sporadic case of HD in which a paternally derived normal length allele expanded to an affected length allele. Linkage analysis and paternity testing confirm the paternal origin of the expansion and demonstrate that unequal crossing over during meiosis is an unlikely mechanism for de novo expansion in HD. This case identifies a complex genetic counseling issue for the families of sporadic cases since calculations of recurrence risk are not possible at this time. In addition, we describe utilization of a combination of polymerase chain reaction (PCR) based assays for examination of both the CAG repeat and an adjacent variable length CCG repeat in the huntingtin gene. The combination of these assays can increase the accuracy of molecular diagnosis for HD and may clarify any ambiguous results obtained during molecular testing of HD families.

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...…”

Trinucleotide Repeat Instability: Genetic Features and Molecular Mechanisms

“…Studies of somatic mosaicism in the other CAG repeat diseases have shown that this initial association was purely coincidental. For DWLA, SCAl and SC.43, the longest repeat expansions are observed in the cerebrum, and the smallest expansions occur in the cerebellum (5,19,49,84,124,131). These profiles are idenl.ica1 to those seen in CNS tissues in HD, although different populations of neurons degenerate in all four of these diseases.…”

Huntington’s disease and striatal signaling

“…Such alleles do not cause HD but show instability on replication and tend to expand in successive generation with greater instability in spermatogenesis than in oogenesis (Zuhlke et al, 1993; Ranen et al, 1995). This instability of increased number of CAG repeats over successive generations explains the phenomenon of genetic anticipation, which is defined by the tendency of an earlier disease onset in successive generations (Goldberg et al, 1993; Myers et al, 1993; Alford et al, 1996). The age of onset cannot be predicted from the CAG repeat length in clinical practice.…”