As these GEITP pages have continued to emphasize, there are (relatively) monogenic diseases (Mendelian disorders) and there are human complex diseases [multifactorial traits that reflect contributions by genetics (DNA sequence alterations), epigenetic factors (not involving DNA mutations), environmental effects (e.g. diet, smoking), endogenous influences (e.g. cardiopulmonary disease or renal function), and each individual’s microbiome]. Autism spectrum disorder (ASD) is a great example of a “complex disease” — clinically and etiologically heterogeneous, and for which a unifying pathophysiology has not yet been identified — for either the disorder as a whole, or its core behavioral components. Heritability estimates are high (between 0.65 and 0.91), based on family and twin studies. Elucidation of the complex genetic architecture (i.e. the underlying genetic basis of a any phenotypic trait and its variational properties) of ASD has, in recent years, revealed contributions from both rare and common DNA variants.
Chromosomal microarray, and next-generation sequencing (NGS), studies have identified many de novo and inherited rare variants of large-effect size that contribute substantially to the etiology of ASD. It has also become clear that pathogenic variants in the same genes are identified in individuals with a variety of different clinically defined brain disorders [i.e. not only ASD but also intellectual disability (ID), epilepsy, schizophrenia, and other neurodevelopmental and neuropsychiatric conditions]. The known collective contribution of rare large-effect pathogenic variants is greatest for neurodevelopmental disorders (NDDs) — such as ID, ASD, and epilepsy — but they are also important etiologic factors in other conditions with onset in childhood (e.g. attention-deficit/hyperactivity disorder [ADHD]) or adolescence (e.g. schizophrenia) and, to a lesser degree, to later-onset neuropsychiatric conditions (e.g. mood disorders).
Authors [see attached Commentary], in a very objective fashion, review the advances and limitations of recent efforts to identify relatively ‘‘autism-specific’’ genes — efforts which focus on rare variants of large-effect size that are thought to account for the observed phenotypes. Authors rigorously question some of the interpretations of published evidence. They also discuss practical and theoretical issues related to studying the relationships between rare large-effect deleterious variants and neurodevelopmental phenotypes. Finally, authors describe potential future directions of this research. Authors argue that there is currently insufficient evidence to establish meaningful ASD specificity of any genes — based on all the large-effect rare-variant data…!!! ☹
Am J Hum Genet May 2020; 106, 587–595