Linkage analysis of a large African family segregating stuttering suggests polygenic inheritance

Raza, Muhammad Hashim; Gertz, E. Michael; Mundorff, Jennifer; Lukong, Joseph; Kuster, Judith Maginnis; Schäffer, Alejandro A.; Drayna, Dennis

doi:10.1007/s00439-012-1252-5

Cited by 37 publications

(34 citation statements)

References 44 publications

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“…In this family, no single chromosomal locus generated significant linkage scores in the full pedigree. However analysis of different combinations of sub-pedigrees generated significant evidence for linkage on chromosomes 2p, 3p, 3q, and 14 under a recessive mode of inheritance [20]. This suggested that, like other studies in non-consanguineous families, no single highly penetrant gene variant was responsible for the many cases of stuttering observed in this family.…”

Section: Genetic Studies Of Stutteringmentioning

confidence: 59%

A role for inherited metabolic deficits in persistent developmental stuttering

Kang

Drayna

2012

Molecular Genetics and Metabolism

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Stuttering is a common but poorly understood speech disorder. Consistent evidence for the involvement of genetic factors in stuttering has motivated studies aimed at identifying causative genetic variants that could shed light on the underlying molecular and cellular deficits in this disorder. Such studies have begun to identify causative genes. The purpose of this review is to summarize the gene discoveries to date, and to cover the subsequent functional studies that are beginning to provide insights into how these gene mutations might cause stuttering. Surprisingly, the first variant genes to be associated with stuttering are those encoding the lysosomal targeting system, GNPTAB, GNPTG, and NAGPA. Although mutations in NAGPA have not been associated with a disorder in humans, mutations in GNPTAB and GNPTG cause mucolipidosis types II and III, which are rare autosomal recessive lysosomal storage disorders, associated with pathology of bone, connective tissue, liver, spleen, and brain. Analysis of mutations in these genes has so far identified predominantly missense mutations in stuttering, in contrast to the truncating and other mutations that result in very low GNPTAB/G enzyme activity and are historically associated with mucolipidosis. Genetic evidence for the role of lysosomal targeting mutations in stuttering has now been buttressed by biochemical studies of the mutant enzymes found in this disorder. While data on the GlcNAc phosphotransferase encoded by GNPTAB/G remains limited and only suggestive, a study of the enzyme encoded by NAGPA has shown that the mutations found in stuttering reduce the overall cellular activity of this enzyme by about half, and that they result in deficits in intracellular processing and trafficking that lead to a reduced cellular half life. How these deficits result in the presumed speech-specific neuropathology associated with stuttering is not yet known. However these findings have opened several new lines of inquiry, including studies in mice carrying human stuttering mutations, that represent promising approaches to this disorder.

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Section: Genetic Studies Of Stutteringmentioning

confidence: 59%

A role for inherited metabolic deficits in persistent developmental stuttering

Kang

Drayna

2012

Molecular Genetics and Metabolism

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“…There are at least ten published studies presenting methods to explore the predictive values of combinations of SNP alleles of pigmentation phenotypes (skin, eye and hair colour) and presence/absence of freckles [33][34][35][36][37][38][39][40][41][42], two of which [34,40] have already been validated [43][44][45]. Additional research is under development regarding these and other phenotypes, such as estimation of age [46][47][48][49], height [50,51], hair shape [52][53][54], facial features [55,56], baldness [54, 57,58], and adult stuttering [59,60]. Besides physical phenotypes, additional information of individuals can be obtained with some reliability by analysing DNA, such as biogeographical ancestry [61,62] and surname of the sample [6,19,[63][64][65][66][67].…”

Section: Pims For Prediction Of Normal Human Traitsmentioning

confidence: 99%

Predicting Physical Features and Diseases by DNA Analysis: Current Advances and Future Challenges

Cerqueira¹,

Ramallo²,

Hünemeier³

et al. 2016

J Forensic Res

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The 'omics' era and its concomitant technological advances have brought great insight into genetics. One of the most promising fields within human genetics is the prediction of physical traits from analysis of genetic material. Besides the predictive potential of DNA, the traceability of pathogenic agents in the human body through molecular analysis is also a field to be further exploited. In this review, we aim to discuss specific aspects of phenotypic prediction by analysing DNA, with special emphasis on normal variation, and the application of a technology known as 'Forensic DNA Phenotyping' (FDP). We also suggest the term 'Phenotype Informative Markers' (PIMs) to designate any molecular markers responsible for normal or pathological human phenotypic variation. In addition, we raise some recommendations related to forensic genetics, the molecular diagnosis of human diseases, and the traceability of pathogens in the human body, giving special emphasis to the need for validation of these tests with strict protocols. Some relevant concerns about privacy, ethics, and legality of such predictions have also been discussed. Finally, we look at perspectives on the use of epigenetic tools, and quote some examples of what has been done in this specific field.

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“…Linkage studies for persistent stuttering (see Table 1) conducted in several different populations have implicated multiple genomic loci and different modes of inheritance Raza et al 2012Raza et al , 2013Domingues et al 2014). A linkage study in a large consanguineous Pakistani family led to the identification of a linkage peak on chromosome 12 (Kang et al 2010).…”

Section: Stutteringmentioning

confidence: 99%

Insights into the Genetic Foundations of Human Communication

2015

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The human capacity to acquire sophisticated language is unmatched in the animal kingdom. Despite the discontinuity in communicative abilities between humans and other primates, language is built on ancient genetic foundations, which are being illuminated by comparative genomics. The genetic architecture of the language faculty is also being uncovered by research into neurodevelopmental disorders that disrupt the normally effortless process of language acquisition. In this article, we discuss the strategies that researchers are using to reveal genetic factors contributing to communicative abilities, and review progress in identifying the relevant genes and genetic variants. The first gene directly implicated in a speech and language disorder was FOXP2. Using this gene as a case study, we illustrate how evidence from genetics, molecular cell biology, animal models and human neuroimaging has converged to build a picture of the role of FOXP2 in neurodevelopment, providing a framework for future endeavors to bridge the gaps between genes, brains and behavior.

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Linkage analysis of a large African family segregating stuttering suggests polygenic inheritance

Cited by 37 publications

References 44 publications

A role for inherited metabolic deficits in persistent developmental stuttering

A role for inherited metabolic deficits in persistent developmental stuttering

Predicting Physical Features and Diseases by DNA Analysis: Current Advances and Future Challenges

Insights into the Genetic Foundations of Human Communication

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