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Clinical Trial
. 2021 Dec 14;22(24):13439.
doi: 10.3390/ijms222413439.

New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing

Lucia Pia Bruno  1   2 , Gabriella Doddato  1   2 , Floriana Valentino  1   2 , Margherita Baldassarri  1   2 , Rossella Tita  3 , Chiara Fallerini  1   2 , Mirella Bruttini  1   3 , Caterina Lo Rizzo  3 , Maria Antonietta Mencarelli  3 , Francesca Mari  1   2   3 , Anna Maria Pinto  3 , Francesca Fava  1   2   3 , Alessandra Fabbiani  1   2   3 , Vittoria Lamacchia  1   2   3 , Anna Carrer  1   2   3 , Valentina Caputo  1   2   3 , Stefania Granata  1   2   3 , Elisa Benetti  2 , Kristina Zguro  2 , Simone Furini  2 , Alessandra Renieri  1   2   3 , Francesca Ariani  1   2   3
Affiliations
Clinical Trial

New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing

Lucia Pia Bruno et al. Int J Mol Sci. .

Abstract

Intellectual disability (ID) is characterized by impairments in the cognitive processes and in the tasks of daily life. It encompasses a clinically and genetically heterogeneous group of neurodevelopmental disorders often associated with autism spectrum disorder (ASD). Social and communication abilities are strongly compromised in ASD. The prevalence of ID/ASD is 1-3%, and approximately 30% of the patients remain without a molecular diagnosis. Considering the extreme genetic locus heterogeneity, next-generation sequencing approaches have provided powerful tools for candidate gene identification. Molecular diagnosis is crucial to improve outcome, prevent complications, and hopefully start a therapeutic approach. Here, we performed parent-offspring trio whole-exome sequencing (WES) in a cohort of 60 mostly syndromic ID/ASD patients and we detected 8 pathogenic variants in genes already known to be associated with ID/ASD (SYNGAP1, SMAD6, PACS1, SHANK3, KMT2A, KCNQ2, ACTB, and POGZ). We found four de novo disruptive variants of four novel candidate ASD/ID genes: MBP, PCDHA1, PCDH15, PDPR. We additionally selected via bioinformatic tools many variants in unknown genes that alone or in combination can contribute to the phenotype. In conclusion, our data confirm the efficacy of WES in detecting pathogenic variants of known and novel ID/ASD genes.

Keywords: autism; intellectual disability; whole-exome sequencing.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
(A) Frontal view of proband I (MBP gene; p.(Phe46fs*18)) showing triangular facies, prominent ears, thin upper lip, absent eyebrows, broad nasal bridge, bulbous nasal tip, thin and sparse hair, everted lower lip, advanced hairline; (B) close-up of the arachnodactyly of the hand of proband I; (C) frontal view of proband II (PCDH15 gene; p.(Lys1859Asnfs*)) displaying square-shaped face, deep-set eyes, bilateral underfolded helix, short and stocky neck; (D) lateral view of proband II; (E) frontal view of proband IV (PDPR gene; p.(Gln276*)) showing big and deep-set eyes, wide nasal tip, thin upper lip, chin dimple and macrodontia; (F) lateral view of proband IV.
Figure 1
Figure 1
(A) Frontal view of proband I (MBP gene; p.(Phe46fs*18)) showing triangular facies, prominent ears, thin upper lip, absent eyebrows, broad nasal bridge, bulbous nasal tip, thin and sparse hair, everted lower lip, advanced hairline; (B) close-up of the arachnodactyly of the hand of proband I; (C) frontal view of proband II (PCDH15 gene; p.(Lys1859Asnfs*)) displaying square-shaped face, deep-set eyes, bilateral underfolded helix, short and stocky neck; (D) lateral view of proband II; (E) frontal view of proband IV (PDPR gene; p.(Gln276*)) showing big and deep-set eyes, wide nasal tip, thin upper lip, chin dimple and macrodontia; (F) lateral view of proband IV.
See this image and copyright information in PMC

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