BACKGROUND AND OBJECTIVES:Behavioral and neuropsychiatric symptoms are frequent in patients with genetic frontotemporal dementia (FTD). We aimed to describe behavioral and neuropsychiatric phenotypes in genetic FTD, quantify their temporal association, and investigate their regional association with brain atrophy. METHODS:We analyzed data of pathogenic variant carriers in the chromosome 9 open reading frame 72 (c9orf72), progranulin (GRN), or microtubule-associated protein tau (MAPT) gene from the Genetic Frontotemporal dementia Initiative cohort study that enrolls both symptomatic pathogenic variant carriers and first-degree relatives of known carriers. Principal component analysis was performed to identify behavioral and neuropsychiatric clusters that were compared with respect to frequency and severity between groups. Associations between neuropsychiatric clusters and MRI-assessed atrophy were determined using voxel-based morphometry. We applied linear mixed effects and generalized linear mixed effects models to assess the longitudinal course of symptoms. RESULTS:A total of 522 participants were included: 221 c9orf72 (138 presymptomatic), 213 GRN (157 presymptomatic), and 88 MAPT (62 presymptomatic) pathogenic variant carriers. Principal component analysis revealed 5 phenotypic clusters (67.6% of variance), labeled diverse behavioral, affective, psychotic, euphoric/hypersexual, and tactile hallucinations phenotype. In participants presenting behavioral or neuropsychiatric symptoms, affective symptoms were most frequent across groups (83.6%-88.1%), followed by diverse behavioral symptoms (68.4%-77.9%). In c9orf72 and GRN pathogenic variant carriers, psychotic symptoms (32.0% and 19.4%, respectively) were more frequent than euphoric/hypersexual symptoms (28.7% and 14.2%, respectively), which was the other way around in MAPT pathogenic variant carriers (28.6% and 23.8%). Although diverse behavioral symptoms were associated with gray and white matter frontotemporal atrophy, only a small atrophy cluster in the right thalamus was associated with psychotic symptoms. Euphoric/hypersexual symptoms were associated with atrophy in mesial temporal lobes, basal forebrain structures, and the striatum (p < 0.05). Estimated time to symptom onset, genetic group, education, and sex influenced behavioral and neuropsychiatric symptoms (p < 0.05). Particularly, in c9orf72 pathogenic variant carriers, psychotic symptoms may be starting decades before recognition of onset of illness. DISCUSSION:We identified multiple clusters of behavioral and neuropsychiatric symptoms in participants with genetic FTD that relate to distinct cerebral atrophy patterns. Their severity depends on time, affected gene, sex, and education. These clinical-genetic associations can guide diagnostic evaluations and the design of clinical trials for new disease-modifying and preventive treatments.

Using genome-wide association data, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's (PD) or Alzheimer's (AD) disease versus controls across ancestry groups. A shared genetic association was observed across diseases at rs601945 (PD: odds ratio (OR)=0.84; 95% confidence interval, [0.80; 0.88]; p=2.2x10-13; AD: OR=0.91[0.89; 0.93]; p=1.8x10-22), and with a protective HLA association recently reported in amyotrophic lateral sclerosis (ALS). Hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03, and absent for HLA-DRB1*04:05. The same signal was associated with decreased neurofibrillary tangles (but not neuritic plaque density) in postmortem brain and was more strongly associated with Tau levels than A{beta}42 levels in the cerebrospinal fluid. Finally, protective HLA-DRB1*04 subtypes strongly bound aggregation-prone Tau PHF6 sequence, but only when acetylated at K311, a modification central to aggregation. A HLA-DRB1*04-mediated adaptive immune response, potentially against Tau, decreases PD, AD and ALS risk, offering the possibility of new therapeutic avenues.

Tecta is a modular, non-collagenous protein of the tectorial membrane (TM), an extracellular matrix of the cochlea essential for normal hearing. Missense mutations in Tecta cause dominant forms of non-syndromic deafness and a genotype-phenotype correlation has been reported in humans, with mutations in different Tecta domains causing mid- or high-frequency hearing impairments that are either stable or progressive. Three mutant mice were created as models for human Tecta mutations; the Tecta(L1820F,G1824D/+) mouse for zona pellucida (ZP) domain mutations causing stable mid-frequency hearing loss in a Belgian family, the Tecta(C1837G/+) mouse for a ZP-domain mutation underlying progressive mid-frequency hearing loss in a Spanish family and the Tecta(C1619S/+) mouse for a zonadhesin-like (ZA) domain mutation responsible for progressive, high-frequency hearing loss in a French family. Mutations in the ZP and ZA domains generate distinctly different changes in the structure of the TM. Auditory brainstem response thresholds in the 8-40 kHz range are elevated by 30-40 dB in the ZP-domain mutants, whilst those in the ZA-domain mutant are elevated by 20-30 dB. The phenotypes are stable and no evidence has been found for a progressive deterioration in TM structure or auditory function. Despite elevated auditory thresholds, the Tecta mutant mice all exhibit an enhanced tendency to have audiogenic seizures in response to white noise stimuli at low sound pressure levels (≤84 dB SPL), revealing a previously unrecognised consequence of Tecta mutations. These results, together with those from previous studies, establish an allelic series for Tecta unequivocally demonstrating an association between genotype and phenotype.

The DFNB1 subtype of autosomal recessive, nonsyndromic hearing impairment, caused by mutations affecting the GJB2 (connection-26) gene, is highly prevalent in most populations worldwide. DFNB1 hearing impairment is mostly severe or profound and usually appears before the acquisition of speech (prelingual onset), though a small number of hypomorphic missense mutations result in mild or moderate deafness of postlingual onset. We identified a novel GJB2 splice-site mutation, c. -22-2A>C, in three siblings with mild postlingual hearing impairment that were compound heterozygous for c. -22-2A>C and c.35delG. Reverse transcriptase-PCR experiments performed on total RNA extracted from saliva samples from one of these siblings confirmed that c. -22-2A>C abolished the acceptor splice site of the single GJB2 intron, resulting in the absence of normally processed transcripts from this allele. However, we did isolate transcripts from the c. -22-2A>C allele that keep an intact GJB2 coding region and that were generated by use of an alternative acceptor splice site previously unknown. The residual expression of wild-type connection-26 encoded by these transcripts probably underlies the mild severity and late onset of the hearing impairment of these subjects.

Already 40 genes have been identified for autosomal-recessive nonsyndromic hearing impairment (arNSHI); however, many more genes are still to be identified. In a Dutch family segregating arNSHI, homozygosity mapping revealed a 2.4 Mb homozygous region on chromosome 11 in p15.1-15.2, which partially overlapped with the previously described DFNB18 locus. However, no putative pathogenic variants were found in USH1C, the gene mutated in DFNB18 hearing impairment. The homozygous region contained 12 additional annotated genes including OTOG, the gene encoding otogelin, a component of the tectorial membrane. It is thought that otogelin contributes to the stability and strength of this membrane through interaction or stabilization of its constituent fibers. The murine orthologous gene was already known to cause hearing loss when defective. Analysis of OTOG in the Dutch family revealed a homozygous 1 bp deletion, c.5508delC, which leads to a shift in the reading frame and a premature stop codon, p.Ala1838ProfsX31. Further screening of 60 unrelated probands from Spanish arNSHI families detected compound heterozygous OTOG mutations in one family, c.6347C>T (p.Pro2116Leu) and c. 6559C>T (p.Arg2187X). The missense mutation p.Pro2116Leu affects a highly conserved residue in the fourth von Willebrand factor type D domain of otogelin. The subjects with OTOG mutations have a moderate hearing impairment, which can be associated with vestibular dysfunction. The flat to shallow "U" or slightly downsloping shaped audiograms closely resembled audiograms of individuals with recessive mutations in the gene encoding a-tectorin, another component of the tectorial membrane. This distinctive phenotype may represent a clue to orientate the molecular diagnosis.

Objective: Recessive mutations of the SLC26A4 (PDS) gene on chromosome 7q31 can cause sensorineural hearing loss with goiter (Pendred syndrome) or non-syndromic autosomal recessive hearing loss (DFNB4). Furthermore, mutations in the GJB2 gene results in autosomal recessive (DFNB1) and dominant (DFNA3) non-syndromic hearing loss. The aim of the present study was to characterize a family with Pendred syndrome affected by severe to profound HL and presenting goiter.Methods: Affected members underwent detailed audiologic examination and characterization. DNA samples from family members were genotyped with polymorphic microsatellite markers and sequencing of the SLC26A4 and GJB2 genes was performed. A total of 25 families with non-syndromic hearing loss were screened for the common p.E47X mutation in the GJB2 gene by direct dideoxy sequencing.Results: Genetic microsatellite analysis showed linkage to the 7q22-q31 chromosomal region and mutation analysis revealed a novel frameshift mutation (c.451delG) in the SLC26A4 gene. Screening of the GJB2 gene in one patient, displayed a homozygous p.E47X mutation, together with a heterozygous c.451delG mutation. Screening of 25 families with HL showed frequent segregation of the p.E47X mutation, which was homozygous in five of these families. Haplotype analysis using microsatellite markers and single nucleotide polymorphisms (SNPs) closely flanking the GJB2 gene, revealed the presence of two disease-associated-haplotypes suggesting the presence of at least, two founder effects carrying the p.E47X non-sense mutation in the Tunisian population.Conclusions: The segregation of both SLC26A4 and GJB2 mutations in the family illustrates once again the unexpected intra-familial genetic heterogeneity in consanguineous families and highlights the difficulty of genetic counselling in such families. In addition, our results disclose the existence of founder effects in the Tunisian population. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

American Journal of Medical Genetics Part AVolume 155, Issue 4 p. 924-927 Research Letter Novel splice-site mutation c.1615-2A>G (IVS14-2A>G) in the SLC26A4 gene causing Pendred syndrome in a consanguineous Portuguese family† Helena Simões-Teixeira, Helena Simões-Teixeira Faculty of Science, Centre for Biodiversity, Functional and Integrative Genomics (BioFIG), University of Lisbon, Lisbon, Portugal Unidad de Genética Molecular, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, SpainSearch for more papers by this authorTiago D. Matos, Tiago D. Matos Faculty of Science, Centre for Biodiversity, Functional and Integrative Genomics (BioFIG), University of Lisbon, Lisbon, PortugalSearch for more papers by this authorMarta Canas Marques, Marta Canas Marques ORL Service, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, EPE, Lisbon, PortugalSearch for more papers by this authorÓscar Dias, Óscar Dias ORL Service, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, EPE, Lisbon, PortugalSearch for more papers by this authorMário Andrea, Mário Andrea ORL Service, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, EPE, Lisbon, PortugalSearch for more papers by this authorEduardo Barreiros, Eduardo Barreiros Endocrinology Department, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, EPE, Lisbon, PortugalSearch for more papers by this authorLuís Barreiros, Luís Barreiros Endocrinology Department, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, EPE, Lisbon, PortugalSearch for more papers by this authorFelipe Moreno, Felipe Moreno Unidad de Genética Molecular, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, SpainSearch for more papers by this authorGraça Fialho, Graça Fialho Faculty of Science, Centre for Biodiversity, Functional and Integrative Genomics (BioFIG), University of Lisbon, Lisbon, PortugalSearch for more papers by this authorHelena Caria, Helena Caria Faculty of Science, Centre for Biodiversity, Functional and Integrative Genomics (BioFIG), University of Lisbon, Lisbon, Portugal Higher School of Health, Polytechnic Institute of Setúbal, Setúbal, PortugalSearch for more papers by this authorIgnacio del Castillo, Corresponding Author Ignacio del Castillo [email protected] Unidad de Genética Molecular, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, SpainUnidad de Genética Molecular, Hospital Ramón y Cajal, Carretera de Colmenar, km 9, 28034 Madrid, Spain.Search for more papers by this author Helena Simões-Teixeira, Helena Simões-Teixeira Faculty of Science, Centre for Biodiversity, Functional and Integrative Genomics (BioFIG), University of Lisbon, Lisbon, Portugal Unidad de Genética Molecular, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, SpainSearch for more papers by this authorTiago D. Matos, Tiago D. Matos Faculty of Science, Centre for Biodiversity, Functional and Integrative Genomics (BioFIG), University of Lisbon, Lisbon, PortugalSearch for more papers by this authorMarta Canas Marques, Marta Canas Marques ORL Service, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, EPE, Lisbon, PortugalSearch for more papers by this authorÓscar Dias, Óscar Dias ORL Service, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, EPE, Lisbon, PortugalSearch for more papers by this authorMário Andrea, Mário Andrea ORL Service, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, EPE, Lisbon, PortugalSearch for more papers by this authorEduardo Barreiros, Eduardo Barreiros Endocrinology Department, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, EPE, Lisbon, PortugalSearch for more papers by this authorLuís Barreiros, Luís Barreiros Endocrinology Department, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, EPE, Lisbon, PortugalSearch for more papers by this authorFelipe Moreno, Felipe Moreno Unidad de Genética Molecular, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, SpainSearch for more papers by this authorGraça Fialho, Graça Fialho Faculty of Science, Centre for Biodiversity, Functional and Integrative Genomics (BioFIG), University of Lisbon, Lisbon, PortugalSearch for more papers by this authorHelena Caria, Helena Caria Faculty of Science, Centre for Biodiversity, Functional and Integrative Genomics (BioFIG), University of Lisbon, Lisbon, Portugal Higher School of Health, Polytechnic Institute of Setúbal, Setúbal, PortugalSearch for more papers by this authorIgnacio del Castillo, Corresponding Author Ignacio del Castillo [email protected] Unidad de Genética Molecular, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, SpainUnidad de Genética Molecular, Hospital Ramón y Cajal, Carretera de Colmenar, km 9, 28034 Madrid, Spain.Search for more papers by this author First published: 17 March 2011 https://doi.org/10.1002/ajmg.a.33740Citations: 3 † How to Cite this Article: Simões-Teixeira H, Matos TD, Marques MC, Dias Ó, Andrea M, Barreiros E, Barreiros L, Moreno F, Fialho G, Caria H, del Castillo I. 2011. Novel splice-site mutation c.1615-2A>G (IVS14-2A>G) in the SLC26A4 gene causing Pendred syndrome in a consanguineous Portuguese family. Am J Med Genet Part A 155:924–927. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat REFERENCES Aravind L, Koonin EV. 2000. The STAS domain—A link between anion transporters and antisigma-factor antagonists. Curr Biol 10: R53–R55. 10.1016/S0960-9822(00)00335-3 CASPubMedWeb of Science®Google Scholar Churbanov A, Rogozin IB, Deogun JS, Ali H. 2006. 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American Journal of Medical Genetics Part AVolume 155, Issue 4 p. fm i-fm v Table of ContentsFree Access Table of Contents, Volume 155, Number 4, April 2011 First published: 24 March 2011 https://doi.org/10.1002/ajmg.a.34033AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume155, Issue4April 2011Pages fm i-fm v RelatedInformation

The prevalence of DFNA8/DFNA12 (DFNA8/12), a type of autosomal dominant nonsyndromic hearing loss (ADNSHL), is unknown as comprehensive population-based genetic screening has not been conducted. We therefore completed unbiased screening for TECTA mutations in a Spanish cohort of 372 probands from ADNSHL families. Three additional families (Spanish, Belgian, and English) known to be linked to DFNA8/12 were also included in the screening. In an additional cohort of 835 American ADNSHL families, we preselected 73 probands for TECTA screening based on audiometric data. In aggregate, we identified 23 TECTA mutations in this process. Remarkably, 20 of these mutations are novel, more than doubling the number of reported TECTA ADNSHL mutations from 13 to 33. Mutations lie in all domains of the a-tectorin protein, including those for the first time identified in the entactin domain, as well as the vWFD1, vWFD2, and vWFD3 repeats, and the D1-D2 and TIL2 connectors. Although the majority are private mutations, four of them-p.Cys1036Tyr, p.Cys1837Gly, p.Thr1866Met, and p.Arg1890Cys-were observed in more than one unrelated family. For two of these mutations founder effects were also confirmed. Our data validate previously observed genotype-phenotype correlations in DFNA8/12 and introduce new correlations. Specifically, mutations in the N-terminal region of a-tectorin (entactin domain, vWFD1, and vWFD2) lead to mid-frequency NSHL, a phenotype previously associated only with mutations in the ZP domain. Collectively, our results indicate that DFNA8/12 hearing loss is a frequent type of ADNSHL. Hum Mutat 32:825-834, 2011. (C) 2011 Wiley-Liss, Inc.