Clinical Targeted Panel Sequencing Analysis in Clinical Evaluation of Children with Autism Spectrum Disorder in China

Abstract

Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder in which genetics play a major role. Molecular diagnosis may lead to a more accurate prognosis, improved clinical management, and potential treatment of the condition. Both copy number variations (CNVs) and single nucleotide variations (SNVs) have been reported to contribute to the genetic etiology of ASD. The effectiveness and validity of clinical targeted panel sequencing (CTPS) designed to analyze both CNVs and SNVs can be evaluated in different ASD cohorts. CTPS was performed on 573 patients with the diagnosis of ASD. Medical records of positive CTPS cases were further reviewed and analyzed. Additional medical examinations were performed for a group of selective cases. Positive molecular findings were confirmed by orthogonal methods. The overall positive rate was 19.16% (109/569) in our cohort. About 13.89% (79/569) and 4.40% (25/569) of cases had SNVs only and CNVs only findings, respectively, while 0.9% (5/569) of cases had both SNV and CNV findings. For cases with SNVs findings, the SHANK3 gene has the greatest number of reportable variants, followed by gene MYT1L. Patients with MYT1L variants share common and specific clinical characteristics. We found a child with compound heterozygous SLC26A4 variants had an enlarged vestibular aqueduct syndrome and autistic phenotype. Our results showed that CTPS is an effective molecular diagnostic tool for ASD. Thorough clinical and genetic evaluation of ASD can lead to more accurate diagnosis and better management of the condition.

Keywords: MYT1L; SLC26A4; autism spectrum disorder; genetic variants; targeted panel sequencing.

Figure 1

The flow of genetic evaluation of 573 cases with autism spectrum disorders in genetic clinics. ASD, autism spectrum disorder; CTPS: clinical targeted panel sequencing; FXS: Fragile X syndrome; SNVs: single nucleotide variations; CNVs, copy number variations; VUS, variant of unknown significance.

Figure 2

(A) The detection yield of SNV and CNV of CTPS in 569 patients. (B) The percentage of SNVs diagnostic variations between males and females. SNVs, single nucleotide variations; CNVs, copy number variations; P, pathogenic; LP, likely pathogenic; VUS, variant of unknown significance.

Figure 3

(A) The locations of variants of patients in the study. Representation based on Protein Paint (Wisteria color: zf-C2HC domain, Turquoise color: MYT1 domain, Orange color: Smc domain) (https://proteinpaint.stjude.org/, accessed on 1 March 2022). The cases correspond with Table 1. (B) (1) The dysmorphic features of case 6 (shown for 1). (2) The Pedigree of family 1. 2 was the father of the patient; 3 was the mother of the patient. The black arrow showed the patient of case 6. (3) SLC26A4 sequence results of patient and his parents. Heterozygous variants of SLC26A4 were identified in the proband (red arrows in patient 1). Both his parents were in a heterozygous state for the variant (paternal: red arrow of 2 for c.1226G>A (p. R409H) in exon 10, maternal: red arrow of 3 for c.2168A>G(p. H723R) in exon 19).