Biallelic mutations in huntington disease: A new case with just one affected parent, review of the literature and terminology. (3rd March 2015)

• Record Type: Journal Article
• Authors: Uhlmann, Wendy R.; Peñaherrera, Maria S.; Robinson, Wendy P.; Milunsky, Jeff M.; Nicholson, Jane M.; Albin, Roger L.
• Is Part Of: American journal of medical genetics. Volume 167:Number 5(2015:May)
• Page Start: 1152
• Page End: 1160
• Publication Date: 2015-03-03
• Subjects: Medical genetics -- Periodicals; 616.14205
• DOI: 10.1002/ajmg.a.37009
• Languages: English
• ISSNs: 1552-4825

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ajmga37009-sec-0001" sec-type="section"> <p>Patients with biallelic mutations for Huntington disease (HD) are rare. We present a 46‐year‐old female with two expanded Huntingtin (<italic>HTT</italic>) alleles with just one known affected parent. This is the first reported patient with molecular studies performed to exclude <italic>HTT</italic> uniparental disomy (UPD). The proband had biparental inheritance of <italic>HTT</italic> alleles (42/44 CAG repeats). Given the negative UPD results, the proband's unaffected mother either had a reduced penetrance allele that expanded into the full mutation range during transmission to our patient or an unknown full <italic>HTT</italic> mutation and died before symptom onset, unlikely given no family history of HD and asymptomatic at age 59. We made the novel observation in our literature review that most patients with biallelic HD did not have two full <italic>HTT</italic> mutations. Most had one <italic>HTT</italic> allele that was in the intermediate or reduced penetrance ranges or 40 CAG repeats, the lowest limit of the full mutation range. Although the number of patients is small, when an allele in these size ranges was present, generally the age of HD onset was in the 50s. If the second <italic>HTT</italic> allele had >45 repeats, then onset was typically 20s–30s. While similar ages of onset have been reported for patients with one or two <italic>HTT</italic> mutations, patients with biallelic mutations may have later onset if an expanded <italic>HTT</italic> allele has ≤40 CAG repeats. Finally, we propose that "biallelic mutations" or "compound heterozygosity" are more accurate descriptive terms than "homozygosity" when there are two non‐identical expanded <italic>HTT</italic> alleles. © 2015 Wiley Periodicals, Inc.</p> </sec> </abstract>