DLG3 Impairment Caused by Missense Variants in Non-Syndromic X-Linked Mental Retardation

Meryem Alagoz (  [email protected] ) Biruni University https://orcid.org/0000-0002-6243-2146 Nasim Kherad Biruni Universitesi Huseyin Avni Solgun Altınbaş Üniversitesi: Altinbas Universitesi Alper Ozkılıc Biruni Universitesi Elif Sibel Aslan Biruni Universitesi Sureyya Bozkurt Istinye University: Istinye Universitesi Şeyda Demirkol Biruni Universitesi Adnan Yuksel Biruni Universitesi

Research Article

Keywords: X- linked Mental Retardation (XLMR), Autism spectrum disease (ASD), Genetics, DLG3 mutation

Posted Date: July 16th, 2021

DOI: https://doi.org/10.21203/rs.3.rs-692598/v1

License:   This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License

Page 1/16 Abstract

X-lined intellectual disability (XLID), formerly known as X-lined mental retardation, is defned as genetically heterogeneous disorders with remarkable cognitive impairment and abnormal adaptive behaviour skills. This study demonstrates the Disc-large homolog 3 (DLG3) gene impairment in 2 different unrelated male probands. The results detected two missense mutations in the DLG3 gene, c.2267 G > A (p.Arg756Gln) and c.2359G > A p. (Gly787Ser) using by NGS. Both mutations were run in the PolyPhen2 program for mutation sensitivity check and showed to have 0.709 and 1, respectively. The familial transmission pattern of MR detected both mothers to be heterozygote. The mutations were shown to have caused non-syndromic XLMR (NS-XLMR) as both males did not show any abnormal facial or physiological features. Based on the IQ measurement, proband 1 and 2’ IQs were measured 40 and 33, and they were diagnosed with moderate and severe XLMR, respectively. Both affected males showed signifcant deterioration in neural development and behaviour abilities, which indicates the signifcant impact of the mutation on neurotransmitters and maintenance of NMDA receptors in neural functions. However, further molecular and functional studies are necessary to provide more conclusive evidence of the detailed abnormalities caused by the reported mutations.

Introduction

Mental retardation (MR) is defned as a genetic disorder with characteristics of below average intellectual functioning and lack of adaptive behaviour (including daily social and practical skills) and manifested in childhood (Bregman, J. D 1991; McDermott et.al 2007). Although the condition is observed in 2–3% of the population, 30–50% of cases cannot be determined etiologically despite thorough IQ score (IQ < 70) and adaptive skills measurements (Baird& Sadovnick 1985; Borthwick-Duffy 1994; Rutter 2006; Flint et.al 1995). Based on IQ, MR is subcategorized into profound (IQ < 20), Severe (IQ: 25–35), Moderate (IQ: 35– 50), Mild (IQ: 50–70), and Borderline (IQ: 70–85) by WHO (World Health Organization) (WHO 1980). Although many factors including pre-, peri-, and post-natal problems (Strømme & Hagberg 2007; Piecuch et.al 1977; Kolevzon et.al 2007; Zoghbi 2003), metabolic disorders such as sphingolipidoses (Scriver 1995; McDermott 2007), iodine defciency (Gaitan & Dunn 1992), and malnutrition (Wines 2006) showed to have caused MR, X-linked gene defects and have been reported to be the signifcant cause as MR incidence rate in males is higher than females (Penrose 1938; Lehrke R.G 1972; Lehrke R.A 1974). The clinical analysis of collected data and linkage studies describes X-linked mental retardation (XLMR) as a highly heterogenous condition with more than 23 identifed XLMR and has an estimated prevalence of 1 in 1,000 males, with fragile X syndrome accounting for 10 to 15% of cases, the prevalence of most other cloned X-linked genes being very low (0.5– 1.0%) with the exception of Aristaless X (Mandel & Chelly 2004). It is classifed as syndromic XLMR (S-XLMR), which accounts for less than 30% of the cases, and non-syndromic