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Spinocerebellar ataxias (SCAs) are inherited neurodegenerative diseases characterized by loss of balance, coordination, and slurred speech. Recently, a digenic mode of inheritance of TBP/STUB1 contributing to SCA was demonstrated. The clinical manifestations of SCATBP/STUB1 include not only ataxia but also obvious cognitive and behavioral impairment. Here, we describe a Chinese family with SCATBP/STUB1 and performed a literature search for similar cases. We identified a Chinese family with SCATBP/STUB1 and compare our clinical findings with other cases described in the literature so far. Four individuals in this family have been found to carry SCATBP/STUB1, of which three have clinical manifestations. A heterozygous deletion mutation in the STIP1-homologous and U-box containing protein 1 (STUB1) gene, NM_005861.4:c433_435del(p.K145del), was identified. The proband is a 34-year-old female with progressive dementia and dysarthria. The mother and uncle of the proband first presented with motor abnormalities and gradually developed cognitive impairment. The proband and her uncle showed cerebellar atrophy on MRI. The proband's brother carried digenic variants but was asymptomatic. SCATBP/STUB1 is a novel SCA subtype. The main clinical manifestations are motor, cognitive, and behavioral abnormalities. Brain MRI shows significant cerebellar atrophy and cortical thinning. The independent segregation of TBP and STUB1 alleles should be considered when evaluating patients with cognitive impairment and ataxia. [ABSTRACT FROM AUTHOR]

Background : Fragile X syndrome (FXS) is the most common form of inherited intellectual disability, caused by CGG-repeats expansion (> 200 repeats). Premutation alleles (PM) (55–200 CGG repeats) are associated with tremor ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and autistic problems. Aim: To screen the frequency of premutation carriers using molecular diagnostic assays, in a cohort of Egyptian males with suspected clinical features of (FXS) checking for the presence of premutation alleles. Methods: The current study comprised 192 Egyptian male children, 92 participants presented with intellectual disability, delayed language development, autistic-like features, behavioral difficulties, anxiety, seizures, and depression compared to 100 healthy males. All cases were subjected to clinical and neuroimaging assessments, when indicated as well as molecular analysis using methylation-specific PCR (MS-PCR) and quantitative real-time PCR (qRT-PCR). Results: Thirty-four premutation carriers out of 92 Egyptian males (37%) of CGG repeats (55 to 200) were illustrated with elevated FMR1 mRNA expression level (p-value < 0.001). Additionally, 2 intermediate (IM) cases (0.03%) (45–55 CGG repeats) showed poor increase in expression level (p-value = 0.02838) plus 6 full mutation (FM) patients (0.07%) with (> 200 CGG repeats) (p-value < 0.001) resulted in FMR1 gene silence. Conclusion: Molecular diagnostic assay including (MS-PCR) and (qRT-PCR) proved to be a sensitive and rapid screening tool for the detection of premutation cases. Furthermore, the presence of positive correlation between FMR1 mRNA expression levels with CGG repeats in premutation cases could serve as a potential diagnostic marker. Application of these diagnostic tools on larger number clinically suspected cases is recommended. [ABSTRACT FROM AUTHOR]

Introduction: There are reports of different clinical statuses in carriers of intermediate alleles (IAs) of CAG trinucleotide repeats in the HTT gene, from individuals affected by a clinical picture indistinguishable from Huntington's disease (HD) to those without manifestations. Therefore, the possible clinical significance of these alleles has been widely debated. Objectives: The aim of this study was to describe general and clinical features and discard HD phenocopies by molecular assessment in a case series of IA carriers on the HTT gene of a laboratory sample from a neurological center in Mexico. Methods: We selected individuals who had previously been tested for the HTT gene expansion, which resulted in IAs. Clinical information was obtained from medical records, and molecular analysis of the JPH3, PRNP, and TBP genes was performed only in IA carriers with clinical manifestations. In addition, two patients with IA and acanthocytes were evaluated by whole-exome sequencing. The scientific and ethical committees of the National Institute of Neurology and Neurosurgery Manuel Velasco Suárez (NINNMVS) approved this study. Results: From 1994 to 2019, the Genetics Department of the NINNMVS confirmed 34 individuals with IAs, 15 of whom belonged to 11 families with HD (IA-HD) and 19 of whom had no family history of HD (IA-non-HD). We found a high proportion of manifestations of the HD phenotypic spectrum in the IA-non-HD subgroup. In addition, among the 20 samples of IA carriers with manifestations molecularly evaluated, we identified two unrelated subjects with CAG/CTG repeat expansions on the JPH3 gene, confirming HD-like 2 (HDL2), and one patient with the homozygous pathogenic c.3232G>T variant (p.Glu1078Ter) in the VPS13A gene, demonstrating choreoacanthocytosis. Discussion/Conclusion: Our results show the most extensive series of subjects with IAs and clinical manifestations. In addition, we identify three HD phenocopies, two HDL2 cases, and one choreoacanthocytosis case. Therefore, we emphasize evaluating other HD phenocopies in IA carriers with clinical manifestations whose family background is not associated with HD. [ABSTRACT FROM AUTHOR]

Objective: HTT is a gene containing a key region of CAG repeats. When expanded beyond 39 repeats, Huntington disease (HD) develops. HTT genes with <35 repeats are not associated with HD. The biological function of CAG repeat expansion below the non-pathological threshold is not well understood. In fact higher number of repeats in HTT confer advantageous changes in brain structure and general intelligence, but several studies focused on establishing the association between CAG expansions and susceptibility to psychiatric disturbances and to other neurodegenerative disease than HD. We hypothesized that HTT CAG repeat length below the pathological threshold might influence mood and personality traits in a longitudinal sample of individuals with Subjective Cognitive Decline. Methods: We included 54 patients with SCD. All patients underwent an extensive neuropsychological battery at baseline, APOE genotyping and analysis of HTT alleles. We used the Big Five Factors Questionnaire (BFFQ) and Hamilton Depression Rating Scale (HDRS), respectively, to assess personality traits of patients and depression at baseline. Patients who did not progress to Mild Cognitive Impairment (MCI) had at least 5-year follow-up time. Results: In the whole sample, CAG repeat number in the shorter HTT allele was inversely correlated with conscientiousness (Pearson = −0.364, p = 0.007). There was no correlation between HDRS and CAG repeats. During the follow-up, 14 patients [25.93% (95% C.I. = 14.24–37.61)] progressed to MCI (MCI+) and 40 [74.07% (95% C.I. = 62.39–85.76)] did not (MCI−). When we performed the same analysis in the MCI+ group we found that: CAG repeat length on the shorter allele was inversely correlated with energy (Pearson = 0.639, p = 0.014) and conscientiousness (Pearson = −0.695, p = 0.006). CAG repeat length on the longer allele was inversely correlated with conscientiousness (Pearson = −0.901, p < 0.001) and directly correlated with emotional stability (Pearson = 0.639, p = 0.014). These associations were confirmed also by multivariate analysis. We found no correlations between BFFQ parameters and CAG repeats in the MCI− group. Discussion: Personality traits and CAG repeat length in the intermediate range have been associated with progression of cognitive decline and neuropathological findings consistent with AD. We showed that CAG repeat lengths in the HTT gene within the non-pathological range influence personality traits. [ABSTRACT FROM AUTHOR]

Abstract Background Huntington disease (HD) (MIM: 143100) is a severe autosomal dominant neurodegenerative disease caused by the expansion of CAG trinucleotides (>35) in the HTT. Objective To investigate the frequency of intermediate CAG alleles (IAs) in individuals residing in Rio de Janeiro city with no familial history of HD (general population, GP) in comparison with a sample of individuals from families presenting with HD who were previously investigated by our group (affected sample, AS). Results The frequency of normal CAG alleles was 96.2%, while that of IAs was 3.6%, and that of reduced penetrance alleles was 0.2% in the GP (n = 470 chromosomes); 7.2% (17/235 individuals) of the GP presented an IA in heterozygosis with a normal allele. There was no statistically significant difference between the frequencies of the IAs in the GP and in the AS (p = .9). The most frequent haplotype per normal allele was (CAG)17‐(CCG)7 (101/461) and per IA was (CAG)27‐(CCG)7 (6/17) in the GP. These haplotypes were also the most frequent in the normal and IA chromosomes of the AS, respectively. Conclusion The genetic profiles of the IAs obtained from GP and AS were rather similar. It is important to investigate the frequencies of the IAs because expansions arise from a step‐by‐step mechanism in which, during intergenerational transmission, large normal alleles can generate IAs, which are then responsible for generating de novo HD mutations. The genetic investigation of IAs in the GP was also important because it was focused on the population of Rio de Janeiro, an understudied group. CCG7 was the most frequent CCG allele in linkage disequilibrium with normal, intermediate, and expanded CAG alleles, similar to the Western Europe population. However, a more robust investigation, in conjunction with haplogroup determination (A, B, or C), will be required to elucidate the ancestral origin of the HTT mutations in Brazilians.

Background: Huntington disease (HD) and spinocerebellar ataxia type 1-2-17 (SCA1-2-17) are adult-onset autosomal dominant diseases, caused by triplet repeat expansions in the HTT, ATXN1, ATXN2, and TBP genes. Alleles with a repeat number just below the pathological threshold are associated with reduced penetrance and meiotic instability and are defined as intermediate alleles (IAs).Objectives: We aimed to determine the frequencies of IAs in healthy Italian subjects and to compare the proportion of the IAs with the prevalence of the respective diseases.Methods: We analyzed the triplet repeat size in HTT, ATXN1, ATXN2, and TBP genes in the DNA samples from 729 consecutive adult healthy Italian subjects.Results: IAs associated with reduced penetrance were found in ATXN2 gene (1 subject, 0.1%) and TBP gene (0.82%). IAs at risk for meiotic instability were found in HTT (5.3%) and ATXN2 genes (2.7%). In ATXN1, we found a low percentage of IAs (0.4%). Alleles lacking the common CAT interruption within the CAG sequence were also rare (0.3%).Conclusions: The high frequencies of IAs in HTT and ATXN2 genes suggest a correlation with the prevalence of the diseases in our population and support the hypothesis that IAs could represent a reservoir of new pathological expansions. On the opposite, ATXN1-IA were very rare in respect to the prevalence of SCA1 in our country, and TBP- IA were more frequent than expected, suggesting that other mechanisms could influence the occurrence of novel pathological expansions. [ABSTRACT FROM AUTHOR]

Background: Huntington disease (HD) (MIM: 143100) is a severe autosomal dominant neurodegenerative disease caused by the expansion of CAG trinucleotides (>35) in the HTT. Objective: To investigate the frequency of intermediate CAG alleles (IAs) in individuals residing in Rio de Janeiro city with no familial history of HD (general population, GP) in comparison with a sample of individuals from families presenting with HD who were previously investigated by our group (affected sample, AS). Results: The frequency of normal CAG alleles was 96.2%, while that of IAs was 3.6%, and that of reduced penetrance alleles was 0.2% in the GP (n = 470 chromosomes); 7.2% (17/235 individuals) of the GP presented an IA in heterozygosis with a normal allele. There was no statistically significant difference between the frequencies of the IAs in the GP and in the AS (p =.9). The most frequent haplotype per normal allele was (CAG)17‐(CCG)7 (101/461) and per IA was (CAG)27‐(CCG)7 (6/17) in the GP. These haplotypes were also the most frequent in the normal and IA chromosomes of the AS, respectively. Conclusion: The genetic profiles of the IAs obtained from GP and AS were rather similar. It is important to investigate the frequencies of the IAs because expansions arise from a step‐by‐step mechanism in which, during intergenerational transmission, large normal alleles can generate IAs, which are then responsible for generating de novo HD mutations. The genetic investigation of IAs in the GP was also important because it was focused on the population of Rio de Janeiro, an understudied group. CCG7 was the most frequent CCG allele in linkage disequilibrium with normal, intermediate, and expanded CAG alleles, similar to the Western Europe population. However, a more robust investigation, in conjunction with haplogroup determination (A, B, or C), will be required to elucidate the ancestral origin of the HTT mutations in Brazilians. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is a rare, hereditary, neurodegenerative and dominantly transmitted disorder affecting about 10 out of 100,000 people in Western Countries. The genetic cause is a CAG repeat expansion in the huntingtin gene (HTT), which is unstable and may further increase its length in subsequent generations, so called anticipation. Mutation repeat length coupled with other gene modifiers and environmental factors contribute to the age at onset in the offspring. Considering the unpredictability of age at onset and of clinical prognosis in HD, the accurate interpretation, a proper psychological support and a scientifically sound and compassionate communication of the genetic test result are crucial in the context of Good Clinical Practice and when considering further potential disease-modifying therapies. We discuss various genetic test scenarios that require a particularly careful attention in psychological and genetic counseling and expect that the counseling procedures will require a constant update.

The Huntingtin gene (HTT) is within a class of genes containing a key region of CAG repeats. When expanded beyond 39 repeats, Huntington disease (HD) develops. Individuals with less than 35 repeats are not associated with HD. Increasing evidence has suggested that CAG repeats play a role in modulating brain development and brain function. However, very few studies have investigated the effect of CAG repeats in the non-pathological range on cognitive performances in non-demented individuals. In this study, we aimed to test how CAG repeats’ length influences neuropsychological scores in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). We included 75 patients (46 SCD and 29 MCI). All patients underwent an extensive neuropsychological battery and analysis of HTT alleles to quantify the number of CAG repeats. Results: CAG repeat number was positively correlated with scores of tests assessing for executive function, visual–spatial ability, and memory in SCD patients, while in MCI patients, it was inversely correlated with scores of visual–spatial ability and premorbid intelligence. When we performed a multiple regression analysis, we found that these relationships still remained, also when adjusting for possible confounding factors. Interestingly, logarithmic models better described the associations between CAG repeats and neuropsychological scores. CAG repeats in the HTT gene within the non-pathological range influenced neuropsychological performances depending on global cognitive status. The logarithmic model suggested that the positive effect of CAG repeats in SCD patients decreases as the number of repeats grows.

Huntington's disease (HD) is a rare, hereditary, neurodegenerative and dominantly transmitted disorder affecting about 10 out of 100,000 people in Western Countries. The genetic cause is a CAG repeat expansion in the huntingtin gene (HTT), which is unstable and may further increase its length in subsequent generations, so called anticipation. Mutation repeat length coupled with other gene modifiers and environmental factors contribute to the age at onset in the offspring. Considering the unpredictability of age at onset and of clinical prognosis in HD, the accurate interpretation, a proper psychological support and a scientifically sound and compassionate communication of the genetic test result are crucial in the context of Good Clinical Practice and when considering further potential disease-modifying therapies. We discuss various genetic test scenarios that require a particularly careful attention in psychological and genetic counseling and expect that the counseling procedures will require a constant update. [ABSTRACT FROM AUTHOR]

Amongst the main reasons people at risk for Huntington's disease (HD) have for undergoing predictive genetic testing are planning a family and prevention of passing on an expanded CAG-repeat to future offspring. After having received an unfavourable test result, a couple may consider prenatal testing in the foetus or preimplantation genetic diagnostic testing (PGD) in embryos. Testing of the foetus or embryos is possible by means of direct testing of the expanded repeat. Optimal reliability in testing the foetus or embryos requires the establishment of the origin of the repeats of both parents in the foetus. For PGD the analysis is combined with or sometimes solely based on identification of the at-risk haplotype in the embryo. This policy implies that in the context of direct testing, the healthy partner's CAG repeat lengths in the HD gene are also tested, but with the expectation that the repeat lengths of the partner are within the normal range, with the proviso that the partner's pedigree is free of clinically confirmed HD. However, recent studies have shown that the expanded repeat has been observed more often in the general population than previously estimated. Moreover, we have unexpectedly observed an expanded repeat in the non-HD partner in four cases which had far-reaching consequences. Hence, we propose that in the context of reproductive genetic counselling, prior to a planned pregnancy, and irrespective of the outcome of the predictive test in the HD-partner, the non-HD partner should also be given the option of being tested on the expanded allele. International recommendations for predictive testing for HD should be adjusted. [ABSTRACT FROM AUTHOR]

Highlights • The genetic role of C9orf72 was previously investigated in MS. • No extensive data are available for the less frequent but more degenerative PPMS disease course. • No pathological repeat expansions were here identified in 198 Italian PPMS patients. • A significant enrichment in intermediate length alleles was found in our PPMS patients. • We provide further evidence that C9orf72 does not play a main role in MS. Abstract Pathological repeat expansion (RE) of the C9orf72 hexanucleotide sequence is associated to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia disease continuum , although other heterogeneous clinical phenotypes have been documented. The occurrence of multiple sclerosis (MS) in some C9orf72 carriers with a more severe ALS disease course has suggested a possible modifying role for MS. However, C9orf72 RE seems not to play a role in MS pathogenesis. In this study, we screened C9orf72 in 189 Italian patients with primary progressive MS (PPMS), a rare clinical form characterized by less inflammation over neurodegenerative features. We failed to detect C9orf72 RE, but a significant representation of intermediate alleles (≥ 20 units) was observed in our PPMS cohort (2.1%) compared to healthy controls (0%, p < 0.05). In the normal range, allele distribution showed a trimodal pattern (2,5,8-repeat units) in PPMS and healthy controls with no significant difference. Our findings further demonstrate that C9orf72 RE is not genetically associated to MS spectrum, but suggest that intermediate alleles may represent risk factors as already reported for Parkinson disease. [ABSTRACT FROM AUTHOR]

Background: Mutations in gene are the most common single genetic cause of autism-spectrum disorders, therefore we investigated the possibility that the intermediate alleles may also contribute to the origin of Autistic disorder. Methods: We screened 96 males, recruited from North West of Iran, who were diagnosed with autistic disease for CGG repeat size. The frequencies of either intermediate or premutation alleles were matched with 168 male controls. All patients and normal controls were of Azeri Turkish ethnicity. Results: Three mutated, five intermediate and four premutation carriers were identified among Autistic patients, compared with one premutation carrier in normal controls, representing a significant excess in small size FMR1 allele carriers (= 0.006). There was also a significant excess of the intermediate carriers compared with normal controls (= 0.006). Conclusions: Both of these alleles may show roles in the etiology of autism, possibly as a result of the rise of mRNA. Considering that there are individuals in the general population are carriers of intermediate and premutation alleles, further screening of larger samples of Autism patients is recommended, in order to estimate the role of small size of CGG repeat alleles in the aetiology of autism. [ABSTRACT FROM AUTHOR]

Most of the early identified brassinosteroid signaling and biosynthetic mutants are null mutants, exhibiting extremely dwarfed phenotypes and male sterility. These null mutants are usually unable to be directly transformed via a routinely used Agrobacterium-mediated gene transformation system and therefore are less useful for genetic characterization of the brassinosteroid (BR)-related pathways. Identification of intermediate signaling mutants such as bri1-5 and bri1-9 has contributed drastically to the elucidation of BR signaling pathway using both genetic and biochemical approaches. However, intermediate mutants of key genes regulating BR biosynthesis have seldom been reported. Here we report identification of several intermediate BR biosynthesis mutants mainly resulted from leaky transcriptions due to the insertions of T-DNAs in the introns. These mutants are semi-dwarfed and fertile and capable to be transformed. These intermediate mutants could be useful tools for future discovery and analyses of novel components regulating BR biosynthesis and catabolism via genetic modifier screen. [ABSTRACT FROM AUTHOR]

Background: Huntington disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion on chromosome 4. Pathology is associated with CAG repeat length. Prior studies examining people in the intermediate allele (IA) range found subtle differences in motor, cognitive, and behavioral domains compared to controls. Objective: The purpose of this study was to examine baseline and longitudinal differences in motor, cognitive, behavioral, functional, and imaging outcomes between persons with CAG repeats in three ranges: normal (≤26), intermediate (27-35), and reduced penetrance (36-39). Methods: We examined longitudinal data from 389 participants in three allele groups: 280 normal controls (NC), 21 intermediate allele [IA], and 88 reduced penetrance [RP]. We used linear mixed models to identify differences in baseline and longitudinal outcomes between groups. Three models were tested: 1) no baseline or longitudinal differences; 2) baseline differences but no longitudinal differences; and 3) baseline and longitudinal differences. Results: Model 1 was the best fitting model for most outcome variables. Models 2 and 3 were best fitting for some of the variables. We found baseline and longitudinal trends of declining performance across increasing CAG repeat length groups, but no significant differences between the NC and IA groups. Conclusion: We did not find evidence to support differences in the IA group compared to the NC group. These findings are limited by a small IA sample size. [ABSTRACT FROM AUTHOR]

Patients with biallelic mutations for Huntington disease (HD) are rare. We present a 46-year-old female with two expanded Huntingtin ( HTT) alleles with just one known affected parent. This is the first reported patient with molecular studies performed to exclude HTT uniparental disomy (UPD). The proband had biparental inheritance of HTT 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 HTT 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 HTT mutations. Most had one HTT 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 HTT allele had >45 repeats, then onset was typically 20s-30s. While similar ages of onset have been reported for patients with one or two HTT mutations, patients with biallelic mutations may have later onset if an expanded HTT 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 HTT alleles. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Intermediate alleles ( IAs) for Huntington disease ( HD) contain 27-35 CAG repeats, a range that falls just below the disease threshold of 36 repeats. While there is no firm evidence that IAs confer the HD phenotype, they are prone to germline CAG repeat instability, particularly repeat expansion when paternally transmitted. Consequently, offspring may inherit a new mutation and develop the disease later in life. Over the last 5 years there has been a renewed interest in IAs. This article provides an overview of the latest research on IAs, including their clinical implications, frequency, haplotype, and likelihood of CAG repeat expansion, as well as patient understanding and current genetic counselling practices. The implications of this growing evidence base for clinical practice are also highlighted. These evidence-based genetic counselling implications may help ensure individuals with an IA predictive test result receive appropriate support, education, and counselling. [ABSTRACT FROM AUTHOR]

In 2001 a program for predictive testing of Spinocerebellar Ataxia type 2 was developed in Cuba, based on the detection of an abnormal CAG trinucleotide repeat expansion in the ATXN2 gene. A descriptive study was designed to assess the implications of ATXN2 large normal and intermediate alleles in the context of the SCA2 Prenatal Diagnosis Program. Four clinical scenarios were selected based upon the behaviour of large normal and intermediate alleles when passing from one generation to the next, showing expansions, contractions, or stability in the CAG repeat size. In some populations, traditional Mendelian risk figures of 0 % or 50 % may not be applicable due to the high frequency of unstable large normal alleles. Couples with no family history of SCA2 may have a >0 % risk of having an affected offspring. Similarly, couples in which there is both an expanded and a large normal allele may have a recurrence risk >50 %. It is imperative that these issues be addressed with these couples during genetic counseling. These recurrence risks have to be carefully estimated in the presence of such alleles (particularly alleles ≥27 CAG repeats), carriers need to be aware of the potential risk for their descendants, and programs for prenatal diagnosis must be available for them. [ABSTRACT FROM AUTHOR]

Centenarians are the best example of successful aging, reaching extreme longevity escaping age-related diseases. Genome sequencing studies provided evidence for genetic factors linked to heathy long life, including genes related to age-dependent diseases. HTT (Huntingtin) gene is linked to Huntington's Disease, but also associated to longevity in capuchins and mice. HTT Intermediate alleles (IAs) are defined as CAG repeat expansion between 27 and 35. According to recent data IAs might increase Alzheimer's Disease risk, but also might have a neuroprotective effect and can confer an advantage in brain development. Here, we investigated, for the first time, the possible implication of HTT IAs in extreme longevity and their possible association in cognitive decline. We analysed the distribution of IAs in Italian Centenarians (n = 143) and compared with pathological controls with cognitive decline (n = 232, including 80 Alzheimer's Disease, 78 Frontotemporal Dementia and 74 Subjective Cognitive Decline patients) and healthy controls (n = 104). Our data show a statistically significant higher frequency of IAs in Centenarians with respect to pathological controls with cognitive decline ( p =.031 ; OR = 2.3097 95% CI 1.0591 to 5.0371), with a percentage of 11.2 respect to 5.4 respectively. The highest presence of IAs in Centenarians confirms and extends in humans a possible implication of HTT gene in exceptional lifespan and in brain development with a neuroprotective effect. • Centenarians showed the highest HTT Intermediate alleles frequency compared to pathological and healthy controls. • Implication of HTT gene in longevity. • HTT Intermediate alleles may have a neuroprotective effect and a role in brain development. [ABSTRACT FROM AUTHOR]

Abstract: Huntington disease is the most frequent polyglutamine disorder with variable worldwide prevalence. Although some Latin American populations have been studied, HD prevalence in Cuban population remains unknown. In order to characterize the disease in Cuba, the relative frequency of HD was determined by studying 130 patients with chorea and 63 unrelated healthy controls, emphasizing in the molecular epidemiology of the disease. Sixty-two patients with chorea belonging to 16 unrelated families carried a pathological CAG expansion in the HTT gene, ranging from 39 to 67 repeats. Eighty-three percent of them come from the eastern region of the country. A significant inverse correlation between age at onset and expanded CAG repeats was seen. Intermediate alleles in affected individuals and controls represented 4.8% and 3.97% respectively, which have been a putative source of de novo mutation. This study represents the largest molecular characterization of Huntington disease in the Cuban population. These results may have significant implications for an understanding of the disease, its diagnosis and prognosis in Cuban patients, giving health professionals the tools to implement confirmatory genetic testing, pre-symptomatic testing and clinical trials in this population. [Copyright &y& Elsevier]

Abstract: Premature ovarian failure (POF) is defined as cessation of menses before the age of 40. The most significant single gene associated with POF is the Fragile X Mental Retardation 1 gene (FMR1). In the present work we screened women with fertility problems from the Basque Country in order to determine, whether in these women, FMR1 CGG repeat size in the intermediate and premutation range was associated with their pathology, and whether intermediate and premutation carriers had endocrine signs of diminished ovarian function, using the most established measure of ovarian reserve, the gonadotropin FSH. A patient sample of 41 women with ovarian insufficiency and a control sample of 32 women with no fertility problems from the Basque Country were examined. The patient sample was classified into three categories according to the results of the retrospective assessment of their ovarian function. In group 2 of patients, women with irregular cycles, reduced fecundity and FSH levels≥10IU/l, there is a significant increase in the number of intermediate and premutation FMR1 alleles (35–54 CGG repeats). In group 3 of patients, women with amenorrhea for at least four consecutive months and FSH levels≥10IU/l, a significant increase in the number of intermediate FMR1 alleles (35–54 CGG repeats) was found in patients compared with controls. In this group all the patients had a serum concentration >40IU/l. The results suggest that in the analysed Basque sample the FMR1 gene has a role in the aetiology of POF. However, elevated FSH levels are more related to the menstrual cycle pattern than to the CGG repeat size. [Copyright &y& Elsevier]

Since the discovery of the genetic mutation underlying Huntington disease (HD) and the development of predictive testing, the genetics of HD has generally been described as straightforward; an individual receives either mutation-positive or negative predictive test results. However, in actuality, the genetics of HD is complex and a small proportion of individuals receive an unusual predictive test result called an intermediate allele (IA). Unlike mutation-positive or negative results, IAs confer uncertain clinical implications. While individuals with an IA will usually not develop HD, there remains an unknown risk for their children and future generations to develop the disorder. The purpose of this study was to explore how individuals understood and interpreted their IA result. Interviews were conducted with 29 individuals who received an IA result and 8 medical genetics service providers. Interviews were analyzed using the constant comparative method and the coding procedures of grounded theory. Many participants had difficulty ' Grasping the Grey' (i.e. understanding and interpreting their IA results) and their family experience, beliefs, expectations, and genetic counseling influenced the degree of this struggle. The theoretical model developed informs clinical practice regarding IAs, ensuring that this unique subset of patients received appropriate education, support, and counseling. [ABSTRACT FROM AUTHOR]

ABSTRACT We assessed the geographical distribution of C9orf72 G4 C2 expansions in a pan- European frontotemporal lobar degeneration ( FTLD) cohort ( n = 1,205), ascertained by the European Early- Onset Dementia ( EOD) consortium. Next, we performed a meta-analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98% in overall FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33% and 20.73%, but also Spain with 25.49%. In contrast, prevalence in Germany was limited to 4.82%. In addition, we studied the role of intermediate repeats (7-24 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss-of-function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC-rich low complexity sequence adjacent to the G4 C2 repeat in C9orf72 expansion carriers ( P < 0.001) with the most common indel creating one long contiguous imperfect G4 C2 repeat, which is likely more prone to replication slippage and pathological expansion. [ABSTRACT FROM AUTHOR]

Background: Huntington's disease (HD) is a devastating heredoneurodegenerative disorder associated with a wide variety of neurological and psychiatric symptoms caused by an expanded CAG repeat in the HTT gene. The expansion mutation in HTT is dominantly transmitted and codes for a protein named huntingtin (htt). Hypothesis: One hypothesis, according to a multistep mechanism, is that the intergenerational transmission of the normal repeat size causes small, progressive CAG stretch elongations in the general population from one generation to another, until a critical pathological CAG repeat threshold is reached. Mutations may originate in the offspring from paternally transmitted CAG repeats, falling within an intermediate alleles (IA) range of 27 to 35 in repeat length. Conclusions: There has been emerging evidence that some individuals with IAs might develop an HD phenotype. This presents a challenge for genetic counseling, because these individuals are often reassured that they are 'disease free.' However, there are many unanswered questions related to the role of IAs in the development of the HD phenotype and in the pathogenesis of HD. © 2012 Movement Disorder Society © 2012 Movement Disorder Society [ABSTRACT FROM AUTHOR]

The article presents a study that revealed experiences of presenting multi-disciplinary research findings to the Huntington disease community. The study discussed the need to balance potential benefits and harms for participants, researchers, and others. It aimed to demonstrate respect for participants' needs, expectations, and priorities.

Sequeiros J, Ramos EM, Cerqueira J, Costa MC, Sousa A, Pinto-Basto J, Alonso I. Large normal and reduced penetrance alleles in Huntington disease: instability in families and frequency at the laboratory, at the clinic and in the population. 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. [ABSTRACT FROM AUTHOR]

Direct mutation analysis for Huntington disease (HD) became possible in 1993 with the identification of an expanded CAG trinucleotide repeat as the mutation underlying the disease. Expansion of CAG length beyond 35 repeats may be associated with the clinical presentation of HD. HD has never been seen in a person with a CAG size of <36 repeats. Intermediate alleles are defined as being below the affected CAG range but have the potential to expand to >35 CAG repeats within one generation. Thus, children of intermediate allele carriers have a low risk of developing HD. Currently, the intermediate allele range for HD is between 27 and 35 CAG repeats. In this study, we review the current knowledge on intermediate alleles for HD including the CAG repeat range, the intermediate allele frequency, and the clinical implications of an intermediate allele predictive test result. The factors influencing CAG repeat expansion, including the CAG size of the intermediate allele, the sex and age of the transmitting parent, the family history, and the HD gene sequence and haplotype, will also be reviewed. [ABSTRACT FROM AUTHOR]

Nine Y-STR loci from the “minimal haplotype” included in Y-STR Haplotype Reference Databases (YHRD) together with eight additional Y-STRs (DYS437, DYS438, DYS439, DYS460, DYS461, GATA C4, GATA H4 and GATA A10) were analyzed in a sample of 101 males from Equatorial Guinea living in Madrid. Haplotype and allelic frequencies were calculated and genetic diversities were estimated for each genetic system as well as for the whole haplotype. An unexpected high frequency (6%) of intermediate alleles (13.2 and 14.2) was found in DYS385. For DYS19, two alleles were found in one sample. Another sample failed to amplify with DYS393 primers using either PowerPlex® Y System (Promega Corporation) or the Y-PLEX™ 12 (Reliagene, New Orleans, LA) commercial kits. Comparison between Equatorial Guinea and another African population (Mozambique; South East Coast) revealed a significant pairwise Φst value between them (Φst = 0.03309; P = 0.00000). [Copyright &y& Elsevier]

There is evidence that male subjects with a clinical picture of action tremor, Parkinsonism, and cerebellar ataxia may have Fragile X premutations (FRAXA). We analyzed FRAXA and FRAXE triplet repeats in 203 male subjects with Parkinson’s disease (PD) and 370 healthy controls. No full mutations or premutations at the FRAXA and FRAXE loci were found in the subjects with PD or in the controls. FRAXA allele distribution was similar in patients and controls. FRAXE intermediate alleles (31–60 repeats CCG) were found in 13 of 203 (6.4%) subjects with PD and in only one of the 370 (0.27%) healthy controls (P < 0.001), thus indicating that these relatively large alleles may be associated with PD. [Copyright &y& Elsevier]

Fragile X syndrome is due to an expanded CGG repeat in the 5' UTR of the FMR1 gene. According to repeat size, we distinguish four allele categories: normal (<40 CGG), intermediate (46-60 CGG), premutated (55-200 CGG) and full mutated (>200 CGG). However, the boundaries among these categories are unclear, making it difficult to classify unstable alleles and to estimate the risk of expansion. We report a family with a proband, carrying a methylated full mutation with an amplification of 1.2?kb. PCR analysis demonstrated two alleles of 29 and 61 CGGs in the mother. Sequencing of the 61 CGG allele showed no AGG interruptions. Both mother's sisters had two alleles of 31 and 44 CGGs, and the daughter of one of these had two alleles of 22 and 44 repeats, demonstrating stable transmission of the 44 CGG allele. The maternal grandfather was deceased, but haplotype reconstruction using markers DXS548 and FRAXAC1 demonstrated that he was carrier of the premutated allele. Furthermore, molecular analysis confirmed the same paternity with a probability of 99.79% for all the three sisters. According to these findings, it is likely that the maternal grandfather carried the 44 CGG allele, showing unstable transmission, given that it expanded first to 61 CGGs in one daughter, and then to full mutation in her child. Although we cannot exclude paternal mosaicism, it is likely that a rare event of progression from an intermediate to a premutated and on to a full mutated allele occurred in this family over two generations.European Journal of Human Genetics (2004) 12, 333-336. doi:10.1038/sj.ejhg.5201154 Published online 21 January 2004 [ABSTRACT FROM AUTHOR]

A cytokine storm, autoimmune features and dysfunctions of myeloid cells significantly contribute to severe coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Genetic background of the host seems to be partly responsible for severe phenotype and genes related to innate immune response seem critical host determinants. The C9orf72 gene has a role in vesicular trafficking, autophagy regulation and lysosome functions, is highly expressed in myeloid cells and is involved in immune functions, regulating the lysosomal degradation of mediators of innate immunity. A large non-coding hexanucleotide repeat expansion (HRE) in this gene is the main genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both characterized by neuroinflammation and high systemic levels of proinflammatory cytokines, while HREs of intermediate length, although rare, are more frequent in autoimmune disorders. C9orf72 full mutation results in haploinsufficiency and intermediate HREs seem to modulate gene expression as well and impair autophagy. Herein, we sought to explore whether intermediate HREs in C9orf72 may be a risk factor for severe COVID-19. Although we found intermediate HREs in only a small portion of 240 patients with severe COVID-19 pneumonia, the magnitude of risk for requiring non-invasive or mechanical ventilation conferred by harboring intermediate repeats >10 units in at least one C9orf72 allele was more than twice respect to having shorter expansions, when adjusted for age (odds ratio (OR) 2.36; 95% confidence interval (CI) 1.04–5.37, p = 0.040). The association between intermediate repeats >10 units and more severe clinical outcome (p = 0.025) was also validated in an independent cohort of 201 SARS-CoV-2 infected patients. These data suggest that C9orf72 HREs >10 units may influence the pathogenic process driving more severe COVID-19 phenotypes. [ABSTRACT FROM AUTHOR]

Intermediate Alleles (IAs) are expansions of CAG repeats in the HTT gene between 27 and 35 repeats which pathogenic meaning remains controversial. They are present in the general population but there is an increasing number of cases with Huntington-like phenotype reported. We reviewed the medical records of cases in our centre where the neurologist suspected Huntington's disease (HD) as one of the feasible diagnoses and genetic testing showed the number of CAG repeats was in the "intermediate range". We gathered the type of symptoms in all cases and the main neuroimaging findings when available. We found 14 cases, 8 males and 6 females, with average age at onset at 64 years old. Most cases exhibited some type of extrapyramidal symptoms. Cognitive and/or behavioral symptoms were also present in most cases (being depression, anxiety and cognitive impairment the most frequent ones). In one case we found deposits of iron in the basal ganglia in the MRI, and in another case we found diffuse cortical hypometabolism with predominantly frontal bilateral involvement and bilateral focal deficit of both caudate and thalamus in the FDG-PET. The clinical and neuroimaging findings of some cases with IA in this series are compatible with the clinical picture of HD but also with several other alternative diagnoses. Therefore we can not establish association between IA and HD. Larger series with more comprehensive diagnostic workout and neuropathological studies are needed to confirm or rule out whether IAs in the HTT gene may cause HD. • We describe the larger series of clinical cases (n = 14) with HD-like phenotype and IAs published to date. • MRI and FDG-PET neuroimaging findings compatible with HD can be found in some patients with IA. • Larger and more detailed series are needed to assess the pathogenic role of IAs in HTT gene. [ABSTRACT FROM AUTHOR]

The Huntingtin gene (HTT) is within a class of genes containing a key region of CAG repeats. When expanded beyond 39 repeats, Huntington disease (HD) develops. Individuals with less than 35 repeats are not associated with HD. Increasing evidence has suggested that CAG repeats play a role in modulating brain development and brain function. However, very few studies have investigated the effect of CAG repeats in the non-pathological range on cognitive performances in non-demented individuals. In this study, we aimed to test how CAG repeats' length influences neuropsychological scores in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). We included 75 patients (46 SCD and 29 MCI). All patients underwent an extensive neuropsychological battery and analysis of HTT alleles to quantify the number of CAG repeats. Results: CAG repeat number was positively correlated with scores of tests assessing for executive function, visual–spatial ability, and memory in SCD patients, while in MCI patients, it was inversely correlated with scores of visual–spatial ability and premorbid intelligence. When we performed a multiple regression analysis, we found that these relationships still remained, also when adjusting for possible confounding factors. Interestingly, logarithmic models better described the associations between CAG repeats and neuropsychological scores. CAG repeats in the HTT gene within the non-pathological range influenced neuropsychological performances depending on global cognitive status. The logarithmic model suggested that the positive effect of CAG repeats in SCD patients decreases as the number of repeats grows. [ABSTRACT FROM AUTHOR]

During the last few years, several studies have reported an excess of intermediate FMR1 alleles in patients with cognitive and/or behavioural phenotypes. Here, we report the frequency of intermediate alleles (IAs) in three pathologies, intellectual disabilities (IDs), attention-deficit/hyperactivity disorder and autism, from different Spanish regions. We found 142 IAs among 9015 patients with ID (1.6%), 4 among the 415 ADHD patients (0.96%) and 4 among the 300 autistic patients (1.3%), similar to the frequency reported in our control population. No evidence was found of an excess of IA at the FRAXA locus in any of the study populations, although geographical variability was detected. Moreover, the analysis of 100 transmissions of IAs showed that 95% of these alleles were stable. Only 3% expanded within the same range and 2% expanded to a full mutation in two generations. No evidence of an association between IAs and behavioural or cognitive phenotypes was found, suggesting that IAs are not clearly implicated in these pathologies. [ABSTRACT FROM AUTHOR]

We analyzed the frequency of intermediate alleles (IAs) in the ATXN1, ATXN2, and HTT genes in several neurodegenerative diseases. The study included 1126 patients with Alzheimer's disease (AD), 440 patients with frontotemporal dementia (FTD), and 610 patients with Parkinson's disease. In all cohorts, we genotyped ATXN1 and ATXN2 CAG repeats. In addition, in the FTD cohort, we determined the number of HTT CAG repeats. The frequency of HTT IAs was higher in patients with FTD (6.9%) versus controls (2.9%) and in the C9orf72 expansion noncarriers (7.2%) versus controls (2.9%), although the difference was nonsignificant after correction for multiple testing. Compared with controls, progressive nonfluent aphasia (PNFA) groups showed a significantly higher frequency of HTT IAs (13.6% vs. 2.9% controls). For the ATXN2 gene, we observed an increase in IA frequency in AD cases (AD 4.1% vs. controls 1.8%) and in the behavioral FTD group (4.8% vs. 1.8%). For the ATXN1 gene, we found a significant increase of IAs in patients with PNFA (18.6%) versus controls (6.7%). In conclusion, our work suggests that the HTT and ATXN1 IAS may contribute to PNFA pathogenesis and point to a link between ATXN2 IAS and AD. • HTT and ATXN1 intermediate alleles (IAs) are associated with progressive nonfluent aphasia. • ATXN2 IAs are increased in Alzheimer's disease and behavioral frontotemporal dementia. • Our results suggest a potential link between IAs with tauopathies. [ABSTRACT FROM AUTHOR]