Molecular Screening Reveals De Novo Loss-of-Function NR4A2 Variants in Saudi Children with Autism Spectrum Disorders: A Single-Center Study
Abstract
:1. Introduction
2. Results
2.1. General Demographic and Clinical Phenotypes of the Study Cohort
2.2. Genetic Analysis: Frequency of De Novo NR4A2 Variants Among Children with ASD
2.3. Molecular Screening of Concordant and Discordant Siblings Reveals Deleterious NR4A2 Variants
2.4. Functional Consequences of the Identified NR4A2 Variants
2.5. Clinical Phenotypes and Intellectual Profiles of NR4A2 Subjects
3. Discussion
4. Materials and Methods
4.1. Study Cohort
4.2. Study Design
4.3. Genetic Analysis and Variant Validation
4.4. Functional Analysis of Splice Region Variants in ASD Patients with Chromosomal Deletions
4.5. Variant Annotation and Classification
4.6. Statistical Analysis
5. Conclusions
6. Limitations of the Study
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ACMG/AMP | American College of Medical Genetics and Genomics and Association for Molecular Pathology |
ADHD | Attention Deficit and Hyperactivity Disorder |
ASD | Autism Spectrum Disorder |
Bp | Base pair |
DBD | DNA-binding domain |
DSM-5 | Diagnostic and Statistical Manual of Mental Disorders (5th edition) |
EDS | Ehlers–Danlos syndrome |
ES | Exome sequencing |
FSIQ | Full-Scale Intelligence Quotient |
IBD | Inflammatory Bowel Disease |
ID | Intellectual disability |
LBD | Ligand binding domain |
LOF | Loss of function |
NDD | Neurodevelopmental delay |
NMD | Nonsense-mediated mRNA decay |
NR4A2 | Nuclear receptor superfamily 4 group A member 2 |
NTD | N-terminal domain |
Nurr1 | Nuclear receptor-related 1 |
NVIQ | Non-Verbal Intelligence Quotient |
OCD | Obsessive–Compulsive Disorder |
PBMCs | Peripheral Blood Mononuclear Cells |
PCR | Polymerase chain reaction |
PPVT | Peabody Picture Vocabulary Test |
RT–PCR | Reverse transcription polymerase chain reaction |
SB-5 | Stanford–Binet Intelligence Scales (5th edition) |
SRS | Social Responsiveness Scale |
VIQ | Verbal Intelligence Quotient |
WGS | Whole-genome sequencing |
WHO | World Health Organization |
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Variable | |
Gender [n, %] | |
Male | 244 (72.19%) |
Female | 94 (27.81%) |
Age (Years) [n, %] | |
3–5 | 74 (21.89%) |
6–9 | 125 (36.98%) |
10–14 | 139 (41.13%) |
Family history | |
Simplex | 293 (93.01%) |
Quad | 21 (6.66%) |
Quintet | 1 (0.317%) |
Total | 315 (100%) |
FSIQ classification [n, %] | |
Average and above IQ (90–129) | 33 (9.76%) |
Low average IQ (80–89) | 59 (17.46%) |
Borderline IQ (70–79) | 74 (21.89%) |
Mildly impaired IQ (55–69) | 84 (24.85%) |
Moderately impaired IQ (40–54) | 72 (21.3%) |
Severely impaired IQ (>35) | 16 (4.74%) |
IQ subscales scoring | |
FSIQ score | 84 (68.5–100.5) * |
VIQ score | 81.5 (63–101.5) |
NVIQ score | 91 (75–104) |
PPVT score | 77 (67.5–88.5) |
SRS score | 77 (67–90) |
Vineland score (AE) | |
<4.5 Years | 102 (97–112) |
>4.5 Years | 69 (57–83) |
Clinical Phenotypes (current) [n, %] | |
Gastrointestinal disorders | 182 (76.47%) |
Sleeping disorders | 165 (48.82%) |
Language/speech impairment | 160 (47.34%) |
Motor difficulties | 148 (43.79%) |
Feeding difficulties | 136 (40.23%) |
Short stature | 77 (22.78%) |
Seizures/epilepsy | 35 (10.35%) |
Autoimmune diseases | 33 (9.76%) |
Facial dimorphism | 17 (5.03%) |
Psychiatric/behavioral problems (current) [n, %] | |
Hyperactivity/ADHD | 185 (54.74%) |
Anxiety | 143 (42.3%) |
Sensory processing difficulties | 123 (36.39%) |
Learning difficulties | 115 (34.02%) |
Attachment disorder | 97 (28.7%) |
OCD | 33 (13.87%) |
Aggressive behavior | 15 (4.43%) |
Proband
(Biosample Accession) | Age (Y)/Sex | Variant (NM_006186.4) | Clingen Identifier/ClinVar Accession | Protein Alteration |
SNV/Indel/
CNV | Protein Domain/Region | ACMG Classification/Evidences | Clinical Phenotypes/Behavioral Problems | Seizures? |
---|---|---|---|---|---|---|---|---|---|
A1 (SAMN43045798) | 6/M | c.-2-2del | VCV003338047.1 | Splicing change | Splice region variant | Intron 2 | Pathogenic (12 ACMG Points: 12P and 0B. PVS, PM2, PP3 (moderate)) | Mild ID, absent speech, mild ataxia, stereotypical body rocking, irregular sleeping, social phobia, attachment disorder, hypersensitivity to external stimuli | No |
c:1del | CA2837995541/VCV003338025.1 | p.(Met1del) | Indel | NTD | Pathogenic (10 ACMG Points: 10P and 0B. PVS1, PM2) | ||||
c.548del | CA645529278, VCV003338477.1 | p.(Pro183Leufs*20) | |||||||
A2 (SAMN43045230) | 11/M | c.44_45insA | CA2837995542, VCV003338013.1 | p.(Ser16Glnfs*28) | Indel | NTD | Pathogenic (10 ACMG Points: 10P and 0B. PVS1, PM2) | Moderate ID, significant language impairment, Rolandic epilepsy, feeding problems, sleeping problems, choreoathetotic movements, incontinence, hyperactivity, learning difficulties | Yes |
c.1159-81_1540+67del | CA2838010100, VCV003338024.1 | p.(Phe387Argfs*19)/Splicing change | CNV | LBD | |||||
A3 (SAMN43045749) | 11/M | c.44_45insA | CA2837995542, VCV003338013.1 | p.(Ser16Glnfs*28) | Indel | NTD | Pathogenic (10 ACMG Points: 10P and 0B. PVS1, PM2) | Mild ID, delayed speech and motor development, mild ataxia, dystonia, chronic dyspepsia and constipation, hyperactivity, anxiety | No |
c.536del | CA2837995544, VCV003338030.1 | p.(Lys179Serfs*24) | |||||||
A6 (SAMN43046049) | 4/F | c.44_45insA | CA2837995542, VCV003338013.1 | p.(Ser16Glnfs*28) | Indel | NTD | Pathogenic (10 ACMG Points: 10P and 0B. PVS1, PM2) | Mild ID, speech dyslexia, delayed walking, mild hypotonia, chronic diarrhea, hyposensitivity to temperature and pain, attachment disorders | No |
c.1159-81_1540+67del | CA2838010100, VCV003338024.1 | p.(Phe387Argfs*19)/Splicing change | CNV | LBD | |||||
A11 (SAMN43045260) | 7/M | c.44_45insA | CA2837995542, VCV003338013.1 | p.(Ser16Glnfs*28) | indel | NTD | Pathogenic (10 ACMG Points: 10P and 0B. PVS1, PM2) | Mild to moderate ID, speech and motor delay, learning difficulties, generalized hypotonia, frequent diarrhea, hypermobile EDS, skin hyperextensibility, mild scoliosis, sleeping problems | Infantile spasms |
c.1159-81_1540+67del | CA2838010100, VCV003338024.1 | p.(Phe387Argfs*19)/Splicing change | CNV | LBD | |||||
A12 (SAMN43046050) | 10/F | c.5_6delCTinsTG | CA2837995543, VCV003338026.1 | p.(Pro2Leu) | SNV | NTD | VUS (3 ACMG points: 3P and 0B. PM2, PP3). SIFT score = 0 (deleterious), PolyPhen score = 0.929 (probably damaging) | Moderate ID, prominent speech impairment, supported walking, overall poor growth, progressive hypotonia, short stature, facial dimorphism, IBD, sleeping disorders | Lennox-Gastaut syndrome |
c.534del | CA2837995545, VCV003338016.1 | p.(Phe178Leufs*25) | Indel | Pathogenic (10 ACMG Points: 10P and 0B. PVS1, PM2) | |||||
c.1159-81_1540+67del | CA2838010100, VCV003338024.1 | p.(Phe387Argfs*19)/Splicing change | CNV | LBD | |||||
AS_12 (SAMN43045274) | 9/M | c.-2-8del | VCV003338474.1 | Non coding | Splice polypyrimidine tract variant | Intron 2 | VUS/Likely Benign (-1 ACMG points: 1P and 2B. BP4, PM2) | Mild ID, speech apraxia, delayed echolalia, choreoathetotic movements, supported walking, IBD, incontinence, anxiety, irregular sleeping | No |
c:1del | CA2837995541/VCV003338025.1 | p.(Met1del) | Indel | NTD | Pathogenic (10 ACMG Points: 10P and 0B. PVS1, PM2) | ||||
A27 (SAMN43045261) | 8/M | c.44_45insA | CA2837995542, VCV003338013.1 | p.(Ser16Glnfs*28) | Indel | NTD | Pathogenic (10 ACMG Points: 10P and 0B. PVS1, PM2) | Mild ID, moderate speech impairment, disproportionate motor development, generalized hypotonia, ataxic gait, anxiety, attachment disorders | No |
c.537G>C | CA348682205, VCV003338475.1 | p.(Lys179Asn) | SNV | VUS (2 ACMG points: 2P and 0B. PM2, PP2). TraP score = 0.338 | |||||
c.1159-81_1540+67del | CA2838010100, VCV003338024.1 | p.(Phe387Argfs*19)/Splicing change | CNV | LBD | Pathogenic (10 ACMG Points: 10P and 0B. PVS1, PM2) | ||||
AS_27 (SAMN43046045) | 5/M | c:1del | CA2837995541/VCV003338025.1 | p.(Met1del) | Indel | NTD | Pathogenic (10 ACMG Points: 10P and 0B. PVS1, PM2) | Mild ID, receptive-expressive language delay, motor delay, mild infantile hypotonia, motor tics, IBD, anxiety, hyperactivity | No |
c.44_45insA | CA2837995542, VCV003338013.1 | p.(Ser16Glnfs*28) | |||||||
A38 (SAMN43045262) | 10/M | c.39A>G | CA429727752 | p.(Gln13=) | Synonymous | NTD | Likely benign (3 ACMG points: 2P and 5B. PM2, PB4, BP7) | Mild to moderate ID, significant language impairment, ataxic gait, dystonia, sleeping disorders, self injury, aggressive behavior | Febrile |
c.44_45insA | CA2837995542, VCV003338013.1 | p.(Ser16Glnfs*28) | Indel | Pathogenic (10 ACMG Points: 10P and 0B. PVS1, PM2) | |||||
c.1159-81_1540+67del | CA2838010100, VCV003338024.1 | p.(Phe387Argfs*19)/Splicing change | CNV | LBD |
Patient (Biosample Accession) | Age (Y)/Sex | Variant (NM_006186.4) | Clingen Identifier/ClinVar Accession | Protein Alteration | SNV/Indel | Protein Domain/Region | ACMG Classification | ACMG Evidences |
---|---|---|---|---|---|---|---|---|
B3_2 (SAMN43942449) | 6/F | c.30_31insG | CA2838140773/ VCV003338478.1 | p.(Ser11Valfs*33) | Indel | NTD | Pathogenic | 10 ACMG Points: 10P and 0B. PVS1, PM2 (moderate) |
B11_2 (SAMN43942450) | 3/F | c.14_15insT | CA2838140772/ VCV003338476.1 | p.(Gln5Hisfs*39) | Indel | Pathogenic | 10 ACMG Points: 10P and 0B. PVS1, PM2 (moderate) | |
B12 (SAMN43942448) | 7/M | c.536_537delCTinsGC | PA2838140774/VCV003338031.1 | p.(Lys179Ser) | SNV | VUS | 2 ACMG points: 2P and 0B. PM2 (moderate) | |
B27 (SAMN43370295) | 4/F | c.5_6delCTinsTG | CA2837995543, VCV003338026.1 | p.(Pro2Leu) | SNV | VUS | 3 ACMG points: 3P and 0B. PM2, PP3). SIFT score = 0 (deleterious), PolyPhen score = 0.929 (probably damaging) | |
c.44_45insA | CA2837995542/VCV003338013.1 | p.(Ser16Glnfs*28) | Indel | Pathogenic | 10 ACMG Points: 10P and 0B. PVS1, PM2 (moderate) | |||
B38 (SAMN43370296) | 6/F | c.39A>G | CA429727752 | p.(Gln13=) | Synonymous | Likely benign | 3 ACMG points: 2P and 5B. PM2 (Supporting), PB4 (strong), BP7 |
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Alharbi, N.M.; Baaboud, W.F.; Shawky, H.; Alrofaidi, A.A.; Farsi, R.M.; Algothmi, K.M.; Hassoubah, S.A.; Basingab, F.S.; Azhari, S.A.; Alharbi, M.G.; et al. Molecular Screening Reveals De Novo Loss-of-Function NR4A2 Variants in Saudi Children with Autism Spectrum Disorders: A Single-Center Study. Int. J. Mol. Sci. 2025, 26, 5468. https://doi.org/10.3390/ijms26125468
Alharbi NM, Baaboud WF, Shawky H, Alrofaidi AA, Farsi RM, Algothmi KM, Hassoubah SA, Basingab FS, Azhari SA, Alharbi MG, et al. Molecular Screening Reveals De Novo Loss-of-Function NR4A2 Variants in Saudi Children with Autism Spectrum Disorders: A Single-Center Study. International Journal of Molecular Sciences. 2025; 26(12):5468. https://doi.org/10.3390/ijms26125468
Chicago/Turabian StyleAlharbi, Najwa M., Wejdan F. Baaboud, Heba Shawky, Aisha A. Alrofaidi, Reem M. Farsi, Khloud M. Algothmi, Shahira A. Hassoubah, Fatemah S. Basingab, Sheren A. Azhari, Mona G. Alharbi, and et al. 2025. "Molecular Screening Reveals De Novo Loss-of-Function NR4A2 Variants in Saudi Children with Autism Spectrum Disorders: A Single-Center Study" International Journal of Molecular Sciences 26, no. 12: 5468. https://doi.org/10.3390/ijms26125468
APA StyleAlharbi, N. M., Baaboud, W. F., Shawky, H., Alrofaidi, A. A., Farsi, R. M., Algothmi, K. M., Hassoubah, S. A., Basingab, F. S., Azhari, S. A., Alharbi, M. G., Yahya, R., & Alhazmi, S. (2025). Molecular Screening Reveals De Novo Loss-of-Function NR4A2 Variants in Saudi Children with Autism Spectrum Disorders: A Single-Center Study. International Journal of Molecular Sciences, 26(12), 5468. https://doi.org/10.3390/ijms26125468