NEGR1 Intragenic Exonic Deletions Strengthen the Association with Neurodevelopmental Disorders
Laboratory Genetics and Genomics
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Primary Categories:
- Laboratory Genetics
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Secondary Categories:
- Laboratory Genetics
Introduction:
The NEGR1 gene, located on the short (p) arm of chromosome 1 at band 1p31.1, encodes the neuronal growth regulator 1 protein, which is one of five members of the IgLON of GPI-anchored cell adhesion molecules and is predominantly expressed in the brain. In mice, homozygous deletion of the Negr1 gene (Negr1−/−) results in impaired social behavior, deficits in reversal learning, and increased anxiety- and depression-like behaviors compared to wild-type littermates. These findings align with multiple Genome-Wide Association Studies in humans, which have strongly linked NEGR1 to depression, obesity, and a broad range of conditions including autism spectrum disorders (ASD), dyslexia, and certain psychiatric disorders. Several NEGR1 intragenic deletions were recently identified in patients with developmental delays, intellectual disability, congenital anomalies/dysmorphisms, and other neurological and behavioral issues. These findings further strengthen the association between NEGR1 and neurodevelopmental disorders, suggesting potential NEGR1 haploinsufficiency. However, limited clinical cases have been comprehensively described, and additional studies are needed to confirm this clinical association and NEGR1 haploinsufficiency.
Methods:
Chromosomal microarray (CMA) analysis, including array comparative genomic hybridization (aCGH) and SNP analysis, was performed using the Agilent 4×180k aCGH+SNP platform. Patients from the literature and DECIPHER database, all involving a NEGR1 intragenic exonic deletion, were also included in this study. A comprehensive review was conducted to analyze these NEGR1 deletions and their associated clinical features. The MANE transcript of NEGR1, specifically NM_173808.3 (RefSeq) or ENST00000357731.10 (Ensembl) comprising seven exons, served as the reference transcript in this study. We searched for the NEGR1 gene in GeneMatcher, but no submissions that matched this search were reported.
Results:
In our cohort of over 12,000 patients studied through CMA, we identified NEGR1 intragenic exonic deletions in three patients, which encompassed exons 1-6, exon 2, and exons 4-6, respectively. Of these three patients, two were young children (aged 8 and 3, respectively), both exhibiting developmental delays. One child also presented with congenital deafness and epilepsy, while the other had hearing loss, microcephaly, mild dilated ventricles, muscle weakness, abnormal gait and mobility, spasticity, oral phase dysphagia, phimosis, and a history of being small for gestational age. The third patient was a newborn girl who presented with complex congenital heart disease, including tricuspid atresia, a severely hypoplastic right ventricle, and hypoplastic left heart syndrome.
Additionally, 22 patients with NEGR1 intragenic exonic deletions were found in the literature (3 patients) and the DECIPHER database (19 patients). It is noteworthy that across all 25 cases, including three patients from our cohort, developmental delay was the most common clinical feature, seen in 11 of 16 patients (68.75%), followed by intellectual disability in 7 of 16 patients (43.75%), strongly suggesting an association with NEGR1 deletions. Congenital anomalies and dysmorphisms were noted in 6 of 17 patients (35.29%), though these features were less recurrent and their link to NEGR1 deletions is uncertain. ASD and Attention-deficit/hyperactivity disorder appeared in 3 of 16 patients (18.75%) each.
Among the 25 patients from our cohort, literature, and the DECIPHER database, there is at least one de novo case and four cases inherited from affected parents. In silico predictions indicate that NEGR1 has a loss-of-function intolerance score (pLI) of 1.00, suggesting a strong likelihood of haploinsufficiency. In the Database of Genomic Variants - Gold Standard Variants and the gnomAD database, only 0.02% of intragenic deletions affected NEGR1 coding regions, primarily impacting exon 1, which is an alternative splice exon.
Conclusion:
Our findings strengthen the association between NEGR1 and neurodevelopmental disorders and add substantial evidence supporting the haploinsufficiency of this gene. Detailed information about our patients' genotypes/phenotypes and comparative analysis of our results and previously published cases with NEGR1 intragenic exonic deletions will be presented.
The NEGR1 gene, located on the short (p) arm of chromosome 1 at band 1p31.1, encodes the neuronal growth regulator 1 protein, which is one of five members of the IgLON of GPI-anchored cell adhesion molecules and is predominantly expressed in the brain. In mice, homozygous deletion of the Negr1 gene (Negr1−/−) results in impaired social behavior, deficits in reversal learning, and increased anxiety- and depression-like behaviors compared to wild-type littermates. These findings align with multiple Genome-Wide Association Studies in humans, which have strongly linked NEGR1 to depression, obesity, and a broad range of conditions including autism spectrum disorders (ASD), dyslexia, and certain psychiatric disorders. Several NEGR1 intragenic deletions were recently identified in patients with developmental delays, intellectual disability, congenital anomalies/dysmorphisms, and other neurological and behavioral issues. These findings further strengthen the association between NEGR1 and neurodevelopmental disorders, suggesting potential NEGR1 haploinsufficiency. However, limited clinical cases have been comprehensively described, and additional studies are needed to confirm this clinical association and NEGR1 haploinsufficiency.
Methods:
Chromosomal microarray (CMA) analysis, including array comparative genomic hybridization (aCGH) and SNP analysis, was performed using the Agilent 4×180k aCGH+SNP platform. Patients from the literature and DECIPHER database, all involving a NEGR1 intragenic exonic deletion, were also included in this study. A comprehensive review was conducted to analyze these NEGR1 deletions and their associated clinical features. The MANE transcript of NEGR1, specifically NM_173808.3 (RefSeq) or ENST00000357731.10 (Ensembl) comprising seven exons, served as the reference transcript in this study. We searched for the NEGR1 gene in GeneMatcher, but no submissions that matched this search were reported.
Results:
In our cohort of over 12,000 patients studied through CMA, we identified NEGR1 intragenic exonic deletions in three patients, which encompassed exons 1-6, exon 2, and exons 4-6, respectively. Of these three patients, two were young children (aged 8 and 3, respectively), both exhibiting developmental delays. One child also presented with congenital deafness and epilepsy, while the other had hearing loss, microcephaly, mild dilated ventricles, muscle weakness, abnormal gait and mobility, spasticity, oral phase dysphagia, phimosis, and a history of being small for gestational age. The third patient was a newborn girl who presented with complex congenital heart disease, including tricuspid atresia, a severely hypoplastic right ventricle, and hypoplastic left heart syndrome.
Additionally, 22 patients with NEGR1 intragenic exonic deletions were found in the literature (3 patients) and the DECIPHER database (19 patients). It is noteworthy that across all 25 cases, including three patients from our cohort, developmental delay was the most common clinical feature, seen in 11 of 16 patients (68.75%), followed by intellectual disability in 7 of 16 patients (43.75%), strongly suggesting an association with NEGR1 deletions. Congenital anomalies and dysmorphisms were noted in 6 of 17 patients (35.29%), though these features were less recurrent and their link to NEGR1 deletions is uncertain. ASD and Attention-deficit/hyperactivity disorder appeared in 3 of 16 patients (18.75%) each.
Among the 25 patients from our cohort, literature, and the DECIPHER database, there is at least one de novo case and four cases inherited from affected parents. In silico predictions indicate that NEGR1 has a loss-of-function intolerance score (pLI) of 1.00, suggesting a strong likelihood of haploinsufficiency. In the Database of Genomic Variants - Gold Standard Variants and the gnomAD database, only 0.02% of intragenic deletions affected NEGR1 coding regions, primarily impacting exon 1, which is an alternative splice exon.
Conclusion:
Our findings strengthen the association between NEGR1 and neurodevelopmental disorders and add substantial evidence supporting the haploinsufficiency of this gene. Detailed information about our patients' genotypes/phenotypes and comparative analysis of our results and previously published cases with NEGR1 intragenic exonic deletions will be presented.