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

• Published in: Human genetics Vol. 132; no. 4; pp. 385 - 396
• Main Authors: Raza, M. Hashim, Gertz, E. Michael, Mundorff, Jennifer, Lukong, Joseph, Kuster, Judith, Schäffer, Alejandro A., Drayna, Dennis
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.04.2013; Springer; Springer Nature B.V
• Subjects: Assortative mating; Biomedical and Life Sciences; Biomedicine; Black People - genetics; Cameroon; chromosome 15; chromosome 2; chromosome 3; Chromosomes; Chromosomes, Human, Pair 15 - genetics; Chromosomes, Human, Pair 3 - genetics; Family; Female; Gene Function; Gene loci; Genetic aspects; Genetic Loci; Genetic Markers; Genomes; Genomics; Human Genetics; Humans; Linkage analysis; Lod Score; Male; Metabolic Diseases; Microsatellites; Middle Aged; Molecular Medicine; Multifactorial Inheritance; Original Investigation; Pedigree; Polygenic inheritance; Polymorphism, Single Nucleotide; Single-nucleotide polymorphism; Speech; Stuttering; Stuttering - genetics; Cameroon; United States > US; Assortative Mating; Penetrance Function; Recessive Locus; Marker Allele Frequency; Full Pedigree
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-012-1252-5

We describe a pedigree of 71 individuals from the Republic of Cameroon in which at least 33 individuals have a clinical diagnosis of persistent stuttering. The high concentration of stuttering individuals suggests that the pedigree either contains a single highly penetrant gene variant or that assortative mating led to multiple stuttering-associated variants being transmitted in different parts of the pedigree. No single locus displayed significant linkage to stuttering in initial genome-wide scans with microsatellite and SNP markers. By dividing the pedigree into five subpedigrees, we found evidence for linkage to previously reported loci on 3q and 15q, and to novel loci on 2p, 3p, 14q, and a different region of 15q. Using the two-locus mode of Superlink, we showed that combining the recessive locus on 2p and a single-locus additive representation of the 15q loci is sufficient to achieve a two-locus score over 6 on the entire pedigree. For this 2p + 15q analysis, we show LOD scores ranging from 4.69 to 6.57, and the scores are sensitive to which marker is chosen for 15q. Our findings provide strong evidence for linkage at several loci.