Genotype–Phenotype Correlations in Relation to Newly Emerging Monogenic Forms of Autism Spectrum Disorder and Associated Neurodevelopmental Disorders: The Importance of Phenotype Reevaluation after Pangenomic Results

Abstract

ASD genetic diagnosis has dramatically improved due to NGS technologies, and many new causative genes have been discovered. Consequently, new ASD phenotypes have emerged. An extensive exome sequencing study carried out by the Autism Sequencing Consortium (ASC) was published in February 2020. The study identified 102 genes which are de novo mutated in subjects affected by autism spectrum disorder (ASD) or similar neurodevelopmental disorders (NDDs). The majority of these genes was already known to be implicated in ASD or NDDs, whereas approximately 30 genes were considered “novel” as either they were not previously associated with ASD/NDDs or very little information about them was present in the literature. The aim of this work is to review the current literature since the publication of the ASC paper to see if new data mainly concerning genotype–phenotype correlations of the novel genes have been added to the existing one. We found new important clinical and molecular data for 6 of the 30 novel genes. Though the broad and overlapping neurodevelopmental phenotypes observed in most monogenic forms of NDDs make it difficult for the clinical geneticist to address gene-specific tests, knowledge of these new data can at least help to prioritize and interpret results of pangenomic tests to some extent. Indeed, for some of the new emerging genes analyzed in the present work, specific clinical features emerged that may help the clinical geneticist to make the final diagnosis by associating the genetic test results with the phenotype. The importance of this relatively new approach known as “reverse phenotyping” will be discussed.

Impaired Neurodevelopmental Genes in Slovenian Autistic Children Elucidate the Comorbidity of Autism With Other Developmental Disorders

“…The introduction of WES in the genetic diagnosis of ASD has significantly improved our knowledge of its etiology at the molecular level. The phenotype-driven analysis is often a limitation in the discovery of new disease-associated genes since the clinical presentation of patients with ASD is a key factor in genetic testing and data interpretation ( Arteche-López et al, 2021 ; Lintas et al, 2021 ). The process of establishing an accurate diagnosis is further hindered by the lack of segregation analysis, reduced penetrance, limited data availability in the literature, as well as non-specific and limited clinical descriptions of patients.…”

“…The process of establishing an accurate diagnosis is further hindered by the lack of segregation analysis, reduced penetrance, limited data availability in the literature, as well as non-specific and limited clinical descriptions of patients. Therefore, reverse phenotyping and seeking the ultrarare variants in genes that are not only limited to ASD and then performing functional studies to obtain datasets should result in a higher diagnostic yield ( Lintas et al, 2021 ).…”

“…NGS methods have also enabled us to pinpoint genes implicated in ASD phenotypes ( Bernier et al, 2014 ; Satterstrom et al, 2020 ). Trio-based WES analysis has proven to be successful in identifying rare inherited and de novo variants in genes involved in the etiology of ASD and novel ASD-associated genes ( Satterstrom et al, 2020 ; Lintas et al, 2021 ). However, the inability to determine the origin of the suspected variant, reduced penetrance, broad clinical characterization of patients with ASD, or lack of clinical information aggravates the process of making proper genotype–phenotype correlations.…”

Expanding the Spectrum of KDM5C Neurodevelopmental Disorder: A Novel De Novo Stop Variant in a Young Woman and Emerging Genotype–Phenotype Correlations

“…Our observations are in line with a recent caregiver report on the characteristics of patients diagnosed with KDM5C variants [ 1 ]: all females had developmental delay and language impairment, 60% had intellectual disability, 70% had short stature, 56% had aggressive behavior, and 44% had anxiety disorder. The clinical geneticist should be aware of these specific clinical features, especially when attempting the interpretation of more variants emerging from WES analysis [ 22 ]. Indeed, reverse phenotyping has become a very useful approach in clinical genetics following the routine implementation of pangenomic tests.…”

The importance of deep speech phenotyping for neurodevelopmental and genetic disorders: a conceptual review

“…Importantly, many published case study descriptions of NDDs, which are identified on the basis of a genomic event (for a review, see [ 59 ]), do not mention the presence of motor speech disorders because they fail to include in the clinical team speech pathologists with the appropriate diagnostic expertise. Instead, most of what we know comes from studies that ascertained cases with motor speech deficits and then carried out genetic testing or were designed to investigate speech in specific genetic cohorts.…”