Biallelic HMGXB4 loss-of-function variant causes intellectual disability, developmental delay, and dysmorphic features
Fuad Al Mutairi,
Faisal Joueidi,
Maha Alshalan,
Essra Aloyouni,
Mariam Ballow,
Mohammed Aldrees,
Abdulkareem Al Abdulrahman,
Abeer Al Tuwaijri,
Safdar Abbas,
Muhammad Umair,
Majid Alfadhel
Affiliations
Fuad Al Mutairi
Genetic and Precision Medicine Department, King Abdullah Specialized Children Hospital, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA), Riyadh, 11426, Saudi Arabia; Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Ministry of National Guard Health Affairs (MNG-HA), Riyadh, 11481, Saudi Arabia; Corresponding author. Genetic and Precision Medicine Department, King Abdullah Specialized Children Hospital, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA), Riyadh, 11426, Saudi Arabia.
Faisal Joueidi
College of Medicine, Al Faisal University, Riyadh, Saudi Arabia
Maha Alshalan
Genetic and Precision Medicine Department, King Abdullah Specialized Children Hospital, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA), Riyadh, 11426, Saudi Arabia
Essra Aloyouni
Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Ministry of National Guard Health Affairs (MNG-HA), Riyadh, 11481, Saudi Arabia
Mariam Ballow
Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Ministry of National Guard Health Affairs (MNG-HA), Riyadh, 11481, Saudi Arabia
Mohammed Aldrees
Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Ministry of National Guard Health Affairs (MNG-HA), Riyadh, 11481, Saudi Arabia
Abdulkareem Al Abdulrahman
Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Ministry of National Guard Health Affairs (MNG-HA), Riyadh, 11481, Saudi Arabia
Abeer Al Tuwaijri
Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Ministry of National Guard Health Affairs (MNG-HA), Riyadh, 11481, Saudi Arabia; Clinical Laboratory Sciences Department, College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, 11426, Saudi Arabia
Safdar Abbas
Department of Biological Sciences, Dartmouth College, Hanover, NH, United States
Muhammad Umair
Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Ministry of National Guard Health Affairs (MNG-HA), Riyadh, 11481, Saudi Arabia
Majid Alfadhel
Genetic and Precision Medicine Department, King Abdullah Specialized Children Hospital, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA), Riyadh, 11426, Saudi Arabia; Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Ministry of National Guard Health Affairs (MNG-HA), Riyadh, 11481, Saudi Arabia
Background: HMGXB4 (additionally known as HMG2L1) is a non-histone DNA-binding protein that contains a single HMG-box domain. HMGXB4 was originally described in Xenopus where it was seen to negatively regulate the Wnt/β-catenin signaling pathway. Materials and methods: In this study, we conducted a genetic and clinical evaluation of a single family with three affected individuals suffering from intellectual disability (ID), global developmental delay (GDD) and dysmorphic facial features.Whole genome sequencing (WGS) and Sanger sequencing were performed on the affected individuals' DNA to identify genetic variations. Additionally, a reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to assess gene expression in both the affected and unaffected individuals in the family. Result: WGS identified a homozygous frameshift variant c.1193_1196del p. (Lys398Argfs × 25) in exon 5 of the HMGXB4 gene (OMIM 604702), which completely segregated the disease phenotype in the family. Furthermore, RT-qPCR revealed a substantial decrease in the HMGXB4 gene expression in the affected individuals as compared to the unaffected individuals of the family. Conclusions: The current study is the first evidence linking a genetic variant in the HMGXB4 gene to ID, GDD, and dysmorphic facial features. Therefore, it is possible that HMGXB4 contributes significantly to developmental milestones and may be responsible for neurodevelopmental disorders in humans.