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

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.

Multilocus disease-causing genomic variations for Mendelian disorders: role of systematic phenotyping and implications on genetic counselling

Multilocus disease-causing genomic variations (MGVs) and multiple genetic diagnoses (MGDs) are increasingly being recognised in individuals and families with Mendelian disorders. This can be mainly attributed to the widespread use of genomic tests for the evaluation of these disorders. We conducted a retrospective study of families evaluated over the last 6 years at our centre to identify families with MGVs and MGDs. MGVs were observed in fourteen families. We observed five different consequences: (i) individuals with MGVs presenting as blended phenotypes (ii) individuals with MGVs presenting with distinct phenotypes (iii) individuals with MGVs with age-dependent penetrance (iv) individuals with MGVs with one phenotype obscured by another more predominant phenotype (v) two distinct phenotypes in different individuals in families with MGVs. Consanguinity was present in eight (8/14, 57.1%) of them. Thirteen families had two Mendelian disorders and one had three Mendelian disorders. The risk of recurrence of one or more conditions in these families ranged from 25% to 75%. Our findings underline the importance of the role of a clinical geneticist in systematic phenotyping, challenges in genetic counselling and risk estimation in families with MGVs and MGDs, especially in highly inbred populations.

Cerebral palsy: not always what it seems

Cerebral palsy (CP) is not a disease, but a neurological syndrome, a combination of signs and symptoms, some of which may occur in neurodegenerative or metabolic disorders, particularly those with an onset in the first 2 years of life. There are many different causes of the syndrome. All children with CP should undergo brain MRI, even with an identified antenatal or perinatal insult. Children with CP should be referred to a paediatric neurologist or a clinical geneticist, or both, if appropriate and particularly in the absence of a known perinatal cerebral insult, with brain MRI that is reported to be normal, a progression in, or new, signs or where there is a reported ‘family history of CP’. Finally, a few of the CP syndromes may be readily treatable and potentially prevent irreversible neurological and cognitive impairment.

Clinical Genetics and Genomics (Oxford Desk Reference)

This book on clinical genetics and genomics includes many common-sense approaches, useful standards and definitions, suggestions for appropriate testing, and excellent references. It is meant to be ‘first-line’ support. It is designed to provide a basic guide to the clinical consultation, be it in outpatients or on the ward, and is intended to be used with other data sources, web resources, and texts. Blank pages are distributed throughout the book to enable the reader to update and personalize the copy with notes from current journals, guidelines, seminars, and lectures. Medical genetics trainees, residents, and fellows should particularly find this book useful; the mature and experienced clinical geneticist should also find it useful and thoughtfully constructed.