European Journal of Medical Genetics xxx (2014) 1e3

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Clinical report

A new mutation for Huntington disease following maternal transmission of an intermediate allele Alicia Semaka a, Chris Kay a, René D.M. Belfroid b, Emilia K. Bijlsma b, Monique Losekoot b, Irene M. van Langen c, Merel C. van Maarle d, Mayke Oosterloo e, f, Michael R. Hayden a, Martine J. van Belzen b, * a

Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands d Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands e Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands f Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 3 July 2014 Accepted 12 November 2014 Available online xxx

New mutations for Huntington disease (HD) originate from CAG repeat expansion of intermediate alleles (27e35 CAG). Expansions of such alleles into the pathological range (36 CAG) have been exclusively observed in paternal transmission. We report the occurrence of a new mutation that defies the paternal expansion bias normally observed in HD. A maternal intermediate allele with 33 CAG repeats expanded in transmission to 48 CAG repeats causing a de novo case of HD in the family. Retrospectively, the mother presented with cognitive decline, but HD was never considered in the differential diagnosis. She was diagnosed with dementia and testing for HD was only performed after her daughter had been diagnosed. This observation of an intermediate allele expanding into the full penetrance HD range after maternal transmission has important implications for genetic counselling of females with intermediate repeats. Ó 2014 Elsevier Masson SAS. All rights reserved.

Keywords: Huntington disease Intermediate allele New mutation Maternal CAG repeat expansion HTT gene

1. Introduction Huntington disease (HD), an autosomal dominant, neurodegenerative disorder, is caused by an expanded CAG repeat tract [The Huntington’s Disease Collaborative Research Group, 1993]. Patients affected have 36 or more repeats in their HTT gene. While often described as an inherited condition, de novo or sporadic cases of HD have been shown to occur [Goldberg et al., 1993]. New mutations result from CAG repeat expansion of intermediate alleles, which have between 27 and 35 CAG repeats. While intermediate alleles are usually stably transmitted, a proportion of transmissions can expand into the affected range, particularly when the allele has a CAG size at the upper end of the intermediate CAG size range, thereby producing a new mutation [Semaka et al., 2010, 2013]. Intermediate alleles have been identified on similar haplotypes compared to HD alleles [Warby

* Corresponding author. Building 2, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. Tel.: þ31 71 526 9810; fax: þ31 71 526 8276. E-mail address: [email protected] (M.J. van Belzen).

et al., 2009]. Intermediate alleles found on these ‘HD-associated’ haplotypes are thought to predispose the allele to CAG repeat expansion. HD-associated haplotypes are predominantly found among Caucasians compared to persons of distinct ethnic backgrounds [Warby et al., 2011]. Until now, all documented cases of new mutations have occurred during paternal intermediate allele transmission. The mechanisms contributing to the parent-of-origin difference in stability of the intermediate repeats are still not clear, but the increased number of cell divisions in male gametogenesis, compared to female may play a role in this bias. Here we describe a new mutation case that conflicts with the paternal sex of the transmitting parent bias normally observed in HD. 2. Clinical report The proband is a 40-year-old Caucasian female with a clinical diagnosis of HD. DNA testing by PCR confirmed the diagnosis by finding 17 and 48 CAG repeats in exon 1 of the HTT gene. Symptoms, which include profound chorea, started around the age of 30 and consecutive MRIs over a 5-year period showed progressive diffuse

http://dx.doi.org/10.1016/j.ejmg.2014.11.005 1769-7212/Ó 2014 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Semaka A, et al., A new mutation for Huntington disease following maternal transmission of an intermediate allele, European Journal of Medical Genetics (2014), http://dx.doi.org/10.1016/j.ejmg.2014.11.005

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atrophy. She had no family history of HD. Her father died shortly after she was diagnosed at the age of 87 years with no signs the disease. Her mother was seen in 1993 at the psychiatry outpatient clinic, 66 years at the time. She presented with cognitive decline. She was known with a mild form of scleroderma. She used no medication. Neurological examination is incomplete in the records but reports no abnormalities. Neuropsychological testing at that moment showed a deterioration compared with an earlier test that year. There were problems with formulating sentences, naming words, writing, verbal fluency and slowness of thinking. Laboratory finding showed a normal ESR, liver and kidney functions, vitamin B1, B12, folium acid, thyroid function and Lues serology. An MRI of the brain was made on which bilateral hippocampal atrophy and numerous old cerebral infarctions were seen. Caudate atrophy was not reported. She was diagnosed with dementia with a degenerative and vascular component. She died in 1997 in a nursing home at the age of 70. The number of HTT CAG repeats were determined post mortem on paraffin coupes sections from the colon. In her status it was noted that her mother had dementia with age of onset over 60 years, but age at death or cause of death of both parents is unknown and also no DNA was available. The two older siblings of the proband show no symptoms of HD and chose not to be tested. Follow-up genetic testing of the proband’s parents revealed her father to be homozygous for 17 CAG repeats and her mother to have 17/33 CAG repeats (Fig. 1). True homozygosity in the father was confirmed by amplifying the CAG repeat, including the adjacent polymorphic CCG repeat (poly-proline) tract, which showed two different repeat sizes in the normal range. The pure size of the adjacent polymorphic CCG repeat tract was also determined both parents were found to have 7 and 10 CCG repeats, whereas the proband was found to be homozygous for 7 CCG repeats (Fig. 1). Sequence analysis confirmed the presence of a normal interrupting sequence between the CAG and CCG tracts, including a penultimate CAA codon for glutamine followed by a terminal CAG in both the parents and the proband. The possibility of nonpaternity, non-maternity, and sample mix-up were also excluded

Fig. 1. Pedigree demonstrating maternal expansion of an intermediate allele with 33 CAG repeats into a disease allele with 48 CAG repeats. The CAG and CCG repeat lengths and haplogroups are defined for each family member. Only family members that were genotyped are depicted in this figure.

using the PowerPlex16 kit (Promega). SNP haplotyping showed that the expansion occurred on a rare HD-associated haplotype, defined as A1x, which closely resembles the previously defined HD-associated haplotype ‘A1’ (Fig. 1) [Warby et al., 2009]. 3. Discussion To our knowledge, this is the first reported case of a maternally transmitted intermediate allele to undergo CAG repeat expansion and produce a new mutation for HD. Paternity/maternity testing, CCG sizing, and haplotype analysis support the finding that the expanded allele in the proband originated from the intermediate allele carried by the mother. It should be noted that the mother’s genotype was determined post-mortally on paraffin embedded colon tissue. This is very unusual, and it is not certain that the number of CAG repeats is identical in blood and colon tissue. In fact, somatic mosaicism of the mutant CAG repeat size has been demonstrated in brain and was shown to be associated with age of onset of the disease. Interestingly, also some somatic instability of the normal repeat was observed [Swami et al., 2009]. Unfortunately nothing is known about mosaicism in colon tissue, but the observed peak pattern of the PCR product of the intermediate allele was similar to those detected in other patients and showed no signs of mosaicism. The phenotypic consequence for carriers of an intermediate allele is still under debate. Prospective studies in cohorts of individuals at risk for HD showed that the intermediate allele was associated with behavioral abnormalities [Killoran et al., 2013], and possibly also motor and cognitive abnormalities [Ha et al., 2012]. On the other hand, several case reports have been published describing patients with symptoms resembling HD [Squitieri and Jankovic, 2012], but strong evidence for a pathological effect of intermediate alleles is still lacking. The mother of the proband presented with cognitive decline, which raises the question whether this could be explained by the intermediate allele. Although neurological examination was incomplete, chorea was not mentioned in her status. The presence of unwanted movements, chorea in particular, is part of the HD phenotype. Furthermore hippocampal atrophy and numerous old cerebral infarctions were seen on MRI. Both abnormalities are characteristic for Alzheimer’s dementia and vascular dementia and it is therefore far more likely that the mother suffered from a combination of these disorders. The frequency of intermediate alleles in the general population is high [Maat-Kievit et al., 2001] and it is therefore likely that the combination of an intermediate allele and neurological symptoms is based on coincidence. However, it cannot be excluded that part of her phenotype may be attributed to the intermediate allele. Since the intermediate allele was found on an HD-associated haplotype, we would expect the allele to demonstrate repeat instability, however, this case defies the paternal expansion bias typically observed for new mutations in HD. While maternal intermediate allele instability has been shown, it occurs at a much lower frequency and magnitude compared to paternal transmission. A study examining familial transmissions found 20% of maternal intermediate alleles were unstable, of which 40% expanded, although not into the disease-associated range [Semaka et al., 2010]. In contrast, 39% of paternal intermediate alleles were shown to be unstable, of which the majority (79%) had expanded. While this is the first documented case of a maternal intermediate allele expanding beyond 36 CAG repeats, maternal expansions of reduced penetrance alleles (36-39 CAG repeats) to full penetrance alleles (>40 CAG repeats) and very large expansions of full penetrance alleles to juvenile HD alleles (60 CAG repeats) have been observed [Sanchez et al., 1997; Laccone and Christian, 2000; Nahhas et al., 2005]. In two cohorts of juvenile HD patients, with

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onset of the disease before age 20, 25e29% of the patients had inherited the disease from the mother, although all infantile cases were of paternal origin [Canella et al., 2004; Ribaï et al., 2007]. The maternal new mutation case presented here may represent a rare event of a maternal intermediate allele expansion or suggests that unknown cis or trans genetic and/or environmental factors may contribute to maternal intermediate allele CAG expansion. While the likelihood remains exceedingly low, the possibility that intermediate alleles may unexpectedly undergo large expansions and produce a new mutation following maternal transmission is important information to share when providing genetic counselling to families identified as having an intermediate allele or new mutation. Acknowledgements Alicia Semaka and Michael R Hayden are supported by the Canadian Institutes of Health Research (CIHR). Alicia Semaka was funded by a Doctoral Award from the CIHR and a Senior Trainee Award from the Michael Smith Foundation for Health Research. Michael R Hayden is a Killam University Professor and holds a Canada Research Chair in Human Genetics and Molecular Medicine. References Cannella M, Gellera C, Maglione V, Giallonardo P, Cislaghi G, Muglia M, et al. The gender effect in juvenile Huntington disease patients of Italian origin. Am J Med Genet B Neuropsychiatr Genet 2004;125:92e8. Goldberg YP, Kremer B, Andrew SE, Theilmann J, Graham RK, Squitieri F, et al. Molecular analysis of new mutations for Huntington’s disease: intermediate alleles and sex of origin effects. Nat Genet 1993;5:174e9. Ha AD, Beck CA, Jankovic J. Tremor Other Hyperkinet Mov, Vol. 2; 2012. http:// tremorjournal.org/article/view/64; 2012.

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Killoran A, Biglan KM, Jankovic J, Eberly S, Kayson E, Oakes D, et al. Characterization of the Huntington intermediate CAG repeat expansion phenotype in PHAROS. Neurology 2013;80:2022e7. Laccone F, Christian W. A recurrent expansion of a maternal allele with 36 CAG repeats causes Huntington disease in two sisters. Am J Hum Genet 2000;66: 1145e8. Maat-Kievit A, Losekoot M, Van Den Boer-Van Den Berg H, Van Ommen GJ, Niermeijer M, Breuning M, et al. New problems in testing for Huntington’s disease: the issue of intermediate and reduced penetrance alleles. J Med Genet 2001;38:E12. Nahhas FA, Garbern J, Krajewski KM, Roa BB, Feldman GL. Juvenile onset Huntington disease resulting from a very large maternal expansion. Am J Med Genet A 2005;137A:328e31. Ribaï P, Nguyen K, Hahn-Barma V, Gourfinkel-An I, Vidailhet M, Legout A, et al. Psychiatric and cognitive difficulties as indicators of juvenile Huntington disease onset in 29 patients. Arch Neurol 2007;646:813e9. Sanchez A, Mila M, Castellvi-Bel S, Rosich M, Jimenez D, Badenas C, et al. Maternal transmission in sporadic Huntington’s disease. Br Med J 1997;62:535e7. Semaka A, Collins JA, Hayden MR. Unstable familial transmissions of Huntington disease alleles with 27-35 CAG repeats (intermediate alleles). Am J Med Genet B Neuropsychiatr Genet 2010;153B:314e20. Semaka A, Kay C, Doty C, Collins JA, Hayden MR. CAG size-specific risk estimates for intermediate allele repeat instability in Huntington disease. J Med Genet 2013;50:696e703. Squitieri F, Jankovic J. Huntington’s disease: how intermediate are intermediate repeat lengths? Mov Disord 2012;27:1714e7. Swami M, Hendricks AE, Gillis T, Massood T, Mysore J, Myers RH, et al. Somatic expansion of the Huntington’s disease CAG repeat in the brain is associated with an earlier age of disease onset. Hum Mol Genet 2009;18:3039e47. The Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 1993;72:971e83. Warby SC, Montpetit A, Hayden AR, Carroll JB, Butland SL, Visscher H, et al. CAG expansion in the Huntington disease gene is associated with a specific and targetable predisposing haplogroup. Am J Hum Genet 2009;84:351e66. Warby SC, Visscher H, Collins JA, Doty CN, Carter C, Butland SL, et al. HTT haplotypes contribute to differences in Huntington disease prevalence between Europe and East Asia. Eur J Hum Genet 2011;19:561e6.

Please cite this article in press as: Semaka A, et al., A new mutation for Huntington disease following maternal transmission of an intermediate allele, European Journal of Medical Genetics (2014), http://dx.doi.org/10.1016/j.ejmg.2014.11.005

A new mutation for Huntington disease following maternal transmission of an intermediate allele.

New mutations for Huntington disease (HD) originate from CAG repeat expansion of intermediate alleles (27-35 CAG). Expansions of such alleles into the...
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