We are continuing linkage studies in an effort to identify the location of genes which predispose individuals to stuttering. To accomplish our initial linkage scan, we plan to enroll 400 affected relative pairs. Over the past year, we made contact with 144 new potential families. From these contacts, we have enrolled 295 new individuals, bringing our total enrollment to 1055 individuals, within which there are 170 affected pairs. Together with other members of these families, we have built our DNA sample collection to 456 individuals, approximately double the number of a year earlier. In collaboration with the Hollins Communications Research Institute, we have also completed clinical evaluation of 331 subjects, to confirm and refine our diagnoses. Completion of these evaluations has revealed a striking difference in the sex ratio of the affected individuals in our families compared to that usually observed in the general stuttering population. While the male:female ratio in the overall stuttering population is approximately 3 or 4, the sex ratio in our families is 1.6. This suggests that genetic causes of stuttering are much less affected by the unknown factors which preferentially predispose males to this disorder. It also provides encouragement for linkage studies, since this potentially confounding phenomenon appears to affect primarily the non-familial cases of stuttering. We have applied for and received access to genotyping services of the Center for Inherited Disease Research, at Johns Hopkins University. Genotyping on the first 100 pairs, which should be sufficient to detect linkage to a single major locus, is scheduled to begin in September 1999.We have been obtaining our DNA samples via buccal swab rather than from blood. Use of our buccal swab procedure greatly lowers barriers to participation and allows us to enroll many individuals who would otherwise refuse. However, the amounts of DNA obtained are much lower than those obtained from blood. Therefore, we have developed reliable methods of whole-genome amplification, along with robust genotyping methods for this amplified DNA. We have initiated pilot genotyping studies to help plan the large-scale genotyping that will be undertaken. Other linkage studies in human communication We have initiated a number of linkage studies in other areas of human communication. With Dr. Christy Ludlow, we have been obtaining blood samples and purifying genomic DNA from families with a number of voice and speech disorders that are known or suspected to be inherited, including vocal fold paralysis and spasmodic dysphonia. Our collection of DNA samples is now a total of 76 individuals in 10 different families, roughly double of that a year ago. We have initially focused our efforts on familial vocal fold paralysis, which is inherited as an autosomal dominant trait in our families. Since this disorder has some features of peripheral neuropathy, we have initially evaluated markers at loci known to contain mutations leading to harcot-Marie- Tooth peripheral neuropathy and spinal muscular atrophy. Genotyping to date has ruled out most of these loci as the location of the cause of vocal fold paralysis. Therefore we believe we have identified a genetically novel peripheral neuropathy which primarily affects the vocal apparatus. We have also become involved in the Utah Genetic Reference Project (UGRP) in an attempt to identify the loci of the genes underlying the two most common specific chemosensory deficits in Caucasians, the ability to taste phenylthiocarbamide (PTC) and the ability to smell androstenone. The UGRP is a re-evaluation of the so-called CEPH families, which have been used for generalized linkage studies and construction of the normal human linkage maps. Since large numbers of genotypesexist for thesefamily members, knowledge of their phenotypes allows linkage studies to be performed without additional laboratory genotyping. In the past year, 15 families have been evaluated for PTC tasting and 14 for the ability to smell androstenone. Six families segregated the ability to taste PTC. Linkage analysis demonstrated strong evidence for a locus on chromosome 7q as the cause of this deficiency in bitter taste. Haplotype analysis has allowed us to identify and narrow the interval in which this gene lies. In addition, significant evidence was also obtained for linkage to other locations in the genome, including chromosomes 5 and 16. These results are being prepared for publication. Finally, we have developed a test for deficiencies in pitch recognition in humans. We have recorded the test in compact disk format and developed population norms for performance on this test. Preliminary results suggest that this test reliably identifies individuals with deficits in pitch recognition, who exist in the population at the level of about 5%. We have entered a collaboration with the Twins Research Unit at St. Thomas Hospital, London to perform a twins study of this trait and to determine estimates for deficits in pitch recognition.
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