PubMed search for Dr. Stephanie Sherman

Areas of Specialization/Research Interests:
Genetic causes of mental retardation
Nondisjunction of human chromosomes
Genetic mapping of complex traits
Fragile X syndrome

Professional Memberships and Activities:
American Society of Human Genetics
International Genetic Epidemiology Society

Education:
1975-1981 Ph.D. in Human Genetics, Indiana University Medical School
1971-1975 B.S., North Carolina State University

BOARD CERTIFICATION:
1984, Ph.D. Medical Geneticist, American Board of Medical Genetics

Research Description:
Dr. Sherman's research program revolves around two syndromes that are related by their phenotype consequence, mental retardation, but not their genetic etiology. These two syndromes include Down syndrome and the fragile X syndrome. For both, we use a genetic epidemiological approach to answer questions related to the underlying genetic mechanism leading to the syndrome and the resulting phenotype consequences.

Over 95% of cases with Down syndrome are caused by the abnormal segregation of chromosome 21 during the formation of eggs and sperm. This syndrome is the most common identified cause of mental retardation in humans and a major cause of miscarriages in older women. In addition to mental retardation, individuals with Down syndrome have characteristic medical findings that significantly jeopardize their health and survival, including congenital heart defects, gut abnormalities and leukemia. We have established a large population-based study of Down syndrome live births and their parents and have combined cytogenetic, molecular and epidemiological tools to elucidate the cause of this chromosome error and its strong association with increased maternal age (National Down Syndrome Project—NDSP). In addition, we have developed a research program to identify genes and/or environmental exposures that lead to the susceptibility of birth defects, specifically those that occur in high frequency among individuals with Down syndrome relative to the general population. This large undertaking will potentially identify new strategies of clinical intervention and/or prevention.

The fragile X syndrome, a type of inherited mental retardation, is due to the silencing of the FMR1 X-linked gene. In over 98% of cases, the mutation is due to an expansion of an unstable CGG repeat sequence located in the 5' untranslated region of the gene. Once over 200 repeats (full mutations), the FMR1 gene is hypermethylated and consequently no message is transcribed. Originally, no significant phenotype was thought to be associated with the 6% of individuals in the general population who carry long, unmethylated FMR1 repeat tracks, i.e., those alleles with 41-199 repeats that produce FMR1 mRNA and protein (FMRP). However, there is now convincing evidence for an associated phenotype: 21% of women who carry the premutation allele (61-199 repeats) are at risk for premature ovarian failure (POF) while those who carry full mutations have the same risk as the general population (1%). Moreover, preliminary evidence from males indicates that increased levels of FMR1 mRNA and reduced levels of FMRP are associated with increasing repeat number. Based on our previous work and that of others, we have suggested that an increased number of FMR1 repeats may influence an individual's cognitive and behavioral performance. Given the FMR1 gene is known to play a role in normal brain function, examination of a cognitive and behavioral consequence of FMR1 high repeat alleles is an important next step. We have established a large genetic epidemiological study of non-clinically referred individuals with high repeat tracts to study the neurological and neuropsychological consequence of these alleles (Emory Study of Adult Learning—ESAL). For females, we also study hormone levels and reproductive histories to better understand factors related to the risk of premature ovarian failure. In addition, we plan to confirm or refute a recent report suggesting that premutation males may be at risk for late onset cerebellar tremors. Lastly, we think it is imperative to begin to translate this important genetic information on the fragile X syndrome, the most common inherited form of mental retardation, into the public health arena. Because women who carry the premutation are not only at risk for having a child with the fragile X syndrome but also are at risk for POF, we plan to investigate the feasibility of screening women of reproductive age for premutation alleles.