Diagnostic yield of whole‐exome sequencing in non‐syndromic intellectual disability

Abstract

Background Aetiological diagnosis in non‐syndromic intellectual disability (NSID) still poses a diagnostic challenge to clinicians. Methods Screening is currently achieved by chromosomal microarrays followed by whole‐exome sequencing (WES). In search for the aetiological yield of WES in patients with NSID, 59 unrelated patients were studied. Results Among the 59 patients, 44 (74.6%) were from consanguineous unions. Epilepsy was present in 11 (37.9%), behavioural problems in 12 (41.4%) and autistic features in 14 (48.3%). WES analysis resulted in molecular diagnosis in 29 patients (49.2%). Some of the genes were specific for nervous system functioning, like HERC1, TBC1D7, LINS, HECW2, DEAF1, HNMT, DLG3, NRXN1 and HUWE1. Others were ubiquitously expressed genes involved in fundamental cellular processes, like IARS, UBE3A, COQ4, TAF1, SETBP1, ARV1, ZC4H2, KAT6A, ASXL3, THOC6, HNRNPH2, TUBA8 and KIF1A. Twenty‐two (75.8%) were consanguineously married; however, only 12 (41.4%) of the detected genes caused autosomal recessive phenotypes. Conclusions This cohort suggests that recessive genes probably represent an actually smaller subgroup of NSID, even among families with consanguinity. Although in societies with high consanguinity rates, considering the recessive inheritance first seems to be an advantageous strategy, de novo mutations in autosomal dominantly expressed genes represent the major aetiological group in patients with NSID, even among those patients from consanguineous families.

First splicing variant in HECW2 with an autosomal recessive pattern of inheritance and associated with NDHSAL

“…Recently, de novo variants in HECW2 have been recognized as a cause of a neurodevelopmental disorder with hypotonia, seizures, and absent language (NDHSAL; MIM# 617268) (Acharya et al, 2021; Berko et al, 2017; Halvardson et al, 2016; Heide et al, 2021; Kritioti et al, 2021; Lu et al, 2021; Nakamura et al, 2018; Peikes et al, 2021; Ullman et al, 2018; Yanagishita et al, 2021). They have also been associated to autism spectrum disorder (Iossifov et al, 2014; Krumm et al, 2015), developmental disorder (Deciphering Developmental Disorders Study 2015; Deciphering Developmental Disorders Study 2017), intellectual disability (Taşkıran et al, 2021), and epileptic encephalopathy (Euro et al, 2014; Hamdan et al, 2017). Currently, 54 patients from 53 families with 32 missense variants in HECW2 have been published (Table 1).…”

“…Currently, 54 patients from 53 families with 32 missense variants in HECW2 have been published (Table 1). These variants showed an autosomal dominant pattern of inheritance, and most of them were de novo (Acharya et al, 2021; Berko et al, 2017; Deciphering Developmental Disorders Study 2015; Deciphering Developmental Disorders Study 2017; Euro et al, 2014; Halvardson et al, 2016; Hamdan et al, 2017; Heide et al, 2021; Iossifov et al, 2014; Kritioti et al, 2021; Krumm et al, 2015; Lu et al, 2021; Nakamura et al, 2018; Peikes et al, 2021; Taşkıran et al, 2021; Ullman et al, 2018; Yanagishita et al, 2021). Of these 32 variants, 18 are described as pathogenic and 7 as likely pathogenic, the rest being of uncertain significance.…”

“… Note : Krumm et al (2015); (3) Deciphering Developmental Disorders Study (2015); (4) Krumm et al (2015); (5) Halvardson et al (2016); (6) Berko et al (2017); (7) Deciphering Developmental Disorders Study (2017); (8) Hamdan et al (2017); (9) Nakamura et al (2018); (10) Ullman et al (2018); (11) Peikes et al (2021); (12) Lu et al (2021); (13) Taşkıran et al (2021); (14) Yanagishita et al (2021); (15) Acharya et al (2021); (16) Kritioti et al (2021); (17) Heide et al (2021); (18) Krami et al (2022). …”

Discriminative features in White-Sutton syndrome: literature review and first report in Iran

“…Presenting of additional medical signs associated with behavioral symptoms and physical abnormalities is known as syndromic type. In Non-syndromic ID, intellectual deficiencies can appear as a clinical isolation features and signs (Boat and Wu, 2015; Taşkiran et al ., 2021). White Sutton syndrome (WHSUS, OMIM: 616364) is a rare genetic and neurodevelopmental disability with an autosomal dominant mode of inheritance, it means deficits in just one allele of the causative gene may lead to disease (Merriweather et al ., 2022).…”

Diagnóstico de deficiência intelectual sindrômica por sequenciamento de nova geração em famílias consanguíneas

“…Estudos de genômica clínica relatam taxa de diagnóstico molecular de doenças monogênicas entre 40% e 60% dos casos (Field et al, 2021). Recentes estudos confirmam essa taxa de diagnóstico molecular, através de análise de exoma, obtidos para casos de DI em famílias consanguíneas (Rasheed et al, 2021;Taşkıran et al, 2021). Nossos resultados demonstram uma taxa de 2/5, ou seja, aproximadamente 40% dos pacientes investigados com diagnóstico molecular para a DI, embora o número seja muito pequeno para ter significado estatístico.…”