Family Relations in the Genomic Era: Communicating about Intergenerational Transmission of Risk for Disability

Developmental disabilities and sensory impair- ments have a wide range of genetic and envi- ronmental causes. Recognized environmental insults include in utero exposure to infections or teratogens (e.g., alcohol, prescription medica- tions, illegal drugs), birth trauma, and premature birth. Genetic causes range from large genome imbalances (such as Down syndrome, or Tri- somy 21, in which there is an extra copy of an entire chromosome) to something as small as one pathogenic DNA variant in a single gene.Genetic abnormalities can occur de novo (a new genetic abnormality not transmitted from either parent) or they can be inherited in several recognizableMendelianpatterns,includingfrom carrier parents who themselves are apparently healthy but who have an increased risk for a serious health problem in their children. Knowledge about heritable risks has long been of interest to parents. For the most part, carrier testing for inherited disorders historically has been disease specific, focusing on severely disabling or life-threatening conditions such as Tay-Sachs disease and cystic fibrosis. But five recent phenomena have forced a rethinking of views and practices regarding the detection of heritable conditions.PHENOMENA AFFECTING DETECTION OF HERITABLE CONDITIONSMore disorders causing disability are recognized as having an inherited componentBasic research on underlying disease processes has led to the identification of inheritance mechanisms for an increasingly large number of disorders. Bell et al. (2011), drawing on data from the Online Mendelian Inheritance in Man (OMIM), reported that there are 7,028 disorders with a suspected Mendelian inheritance, of which only about 16% (1,139) are autosomal recessive (requiring two carrier parents before the disease is manifest in children).Complex notions of genetic susceptibility and riskGenome-wide association studies are pro- viding new insights into genetic suscepti- bility for conditions such as schizophrenia, bipolar disorder, autism, or attention-deficit/ hyperactivity disorders (ADHD; Gershon & Alliey-Rodriguez, 2013). Genetic susceptibility means that genetic changes have been associ- ated with elevated risk for having the disorder at the population level. But the factors determining whether or how the disorder is expressed in an individual are not well understood.Although many types of intellectual and developmental disabilities are predicted to have an underlying causal genetic component, far fewer cases can be confidently ascribed to a single gene mutation. Although Mendelian forms certainly exist, with the X chromosome harboring many genes crucial for normal brain development, many cases of intellectual disabilities are classified as ''familial.'' This classification assumes that a genetic component is present because of its occurrence in multiple biologic relatives, but the family history does not fit a Mendelian pattern of inheritance of a single gene. Rather, the term multifactorial is commonly used to describe the combination of genetic and environmental factors that occur together in the affected individual. A polygenic risk score has been proposed as a way to summarize genetic effects for traits or conditions in which no single gene is implicated but for which a composite score of multiple genetic components can be calculated to provide an overall summary of heritability (Dudbridge, 2013). Because members of a family share many alleles (versions of a gene) as well as many environmental factors in common, it is oftendifficulttountangletheirrelevantcausative roles. Hamshere et al. (2013) provide a recent example of how a polygenic risk score is associated with ADHD, an association that is further strengthened if children with ADHD also have comorbid aggression.Other contributions to gene expression or disruptionIt is becoming increasingly apparent that the bio- logical and physical environment can affect gene expression, a phenomenon generally referred to as ''epigenetics'' (cf. …