Targeted next generation sequencing in 112 Chinese patients with intellectual disability/developmental delay: novel mutations and candidate gene

Abstract

Background Intellectual disability/developmental delay is a complex condition with extraordinary heterogeneity. A large proportion of patients lacks a specific diagnosis. Next generation sequencing, enabling identification of genetic variations in multiple genes, has become an efficient strategy for genetic analysis in intellectual disability/developmental delay. Methods Clinical data of 112 Chinese families with unexplained intellectual disability/developmental delay was collected. Targeted next generation sequencing of 454 genes related to intellectual disability/developmental delay was performed for all 112 index patients. Patients with promising variants and their other family members underwent Sanger sequencing to validate the authenticity and segregation of the variants. Results Fourteen promising variants in genes EFNB1, MECP2, ATRX, NAA10, ANKRD11, DHCR7, LAMA1, NFIX, UBE3A, ARID1B and PTPRD were identified in 11 of 112 patients (11/112, 9.82%). Of 14 variants, eight arose de novo , and 13 are novel. Nine patients (9/112, 8.03%) got definite molecular diagnoses. It is the first time to report variants in EFNB1, NAA10, DHCR7, LAMA1 and NFIX in Chinese intellectual disability/developmental delay patients and first report about variants in NAA10 and LAMA1 in affected individuals of Asian ancestry. Conclusions Targeted next generation sequencing of 454 genes is an effective test strategy for patients with unexplained intellectual disability/developmental delay. Genetic heterogenicity is significant in this Chinese cohort and de novo variants play an important role in the diagnosis. Findings of this study further delineate the corresponding phenotypes, expand the mutation spectrum and support the involvement of PTPRD in the disease. Electronic supplementary material The online version of this article (10.1186/s12881-019-0794-y) contains supplementary material, which is available to authorized users.

Whole genome sequencing of 45 Japanese patients with intellectual disability

“…Overall, our detection rate for the pathogenic and likely pathogenic variants were limited to 27% because we scanned for variants only in the coding regions. Previous studies on ID using high‐throughput DNA sequencing revealed a conclusive diagnostic rate as 8.0–34.0% (Chérot et al, 2018; Fitzgerald et al, 2015; Gieldon et al, 2018; Han et al, 2018; Lindstrand et al, 2019; Nambot et al, 2018; Wright et al, 2015; Yamamoto et al, 2019; Yan et al, 2019). Of these, one study using WGS revealed a total diagnostic rate of 27%, which was the same as that reported in this study (Lindstrand et al, 2019).…”

“…Of these variants, eight occurred de novo (66.7%), two showed maternally inherited X‐linked patterns (16.7%), one was autosomal dominant (8.3%), and one was transmitted in an autosomal recessive (AR) manner (8.3%). The proportion of inheritance patterns of pathogenic or likely pathogenic variants in previous studies using high‐throughput DNA sequencing analysis differs in frequency study by study from other East Asian and Western European countries, but de novo dominant variants were the most common (55–90%), while maternally inherited X‐linked variants (5–22%) and variants inherited in AR manner (0–22%) have variable frequencies, second only to de novo variants (Chérot et al, 2018; Fitzgerald et al, 2015; Gieldon et al, 2018; Han, Jang, Park, & Lee, 2018; Nambot et al, 2018; Wright et al, 2015; Yamamoto et al, 2019; Yan et al, 2019). Our study in a Japanese ID cohort also showed a high frequency of de novo variants and a similar frequency in X‐linked and AR variants.…”

Clinical and genetic characteristics and prenatal diagnosis of patients presented GDD/ID with rare monogenic causes

“…For etiological diagnosis, according to the guideline proposed by American Psychiatric Association (APA) in 2014 [1] and Chinese Medical Association(CMA) in 2018 [16], all patients underwent systematically examinations, comprising medical history, physical examination, metabolic tests and neuroimaging study (brain MRI/CT) to exclude non genetic causes and underwent necessary genetic tests, such as G-band karyotyping, FMR1 CGG repeat testing [17], and CMA testing [18], to exclude other genetic reasons. Sanger sequencing or Trio-NGS [19,20], including targeted exome sequencing (panel) or whole exome sequencing (WES) was performed depending on clinical judgment. The details of the detection methods are reported elsewhere.…”

A novel exomal ATRX mutation with preferential transmission to offspring: A case report and review of the literature for transmission ratio distortion in ATRX families

“…To investigate the possibility that mutant ATRX alleles were preferentially transmitted to offspring, a meta-analysis of published pedigrees with complete reporting of family structures was conducted. data on transmission of ATRX alleles for 42 mothers were extracted from papers published between 1991 and 2019 (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Probands and index cases were excluded from the calculations, as well as offspring from one mosaic mother.…”