My Variants in Old Dyslexia-Linked Genes

 

This is a blog post about my variants in old Dyslexia-linked genes.    With my being a neurodivergent (having Dyslexia, Dyspraxia, ADHD) with Ataxia, I was very curious about genes associated with Dyslexia. 


This concludes my Developmental Neurogenomics series of blog posts. 

My Neurological Makeup includes both Neurodivergence and Ataxia

https://neurodivergence.blogspot.com/2024/01/my-neurological-makeup-includes-both.html

The DRD4 (Dopamine Receptor D4) Gene

https://neurodivergence.blogspot.com/2024/01/the-drd4-dopamine-receptor-d4-gene.html

My Potential Dyslexia Risk Factors Based On 2022 Published 'Discovery of 42 genome-wide significant loci associated with dyslexia'

https://neurodivergence.blogspot.com/2024/02/my-potential-dyslexia-risk-factors.html

My Potential ADHD Risk Factors based on 2022 Published 'Genome-wide analyses of ADHD identify 27 risk loci'

https://neurodivergence.blogspot.com/2024/03/my-potential-adhd-risk-factors-based-on.html

My Potential Comorbid ADHD-Dyslexia Risk Factors based on 2023 Published 'Associative gene networks reveal novel candidates important for ADHD and dyslexia comorbidity'

https://neurodivergence.blogspot.com/2024/03/my-potential-comorbid-adhd-dyslexia.html

My Rare Single Nucleotide Variants that are shown to be potentially Pathogenic according to In-Silico Predictors

https://neurodivergence.blogspot.com/2024/03/my-rare-single-nucleotide-variants-that.html

My Rare Frameshift Variants That Escape Nonsense-Mediated Decay

https://neurodivergence.blogspot.com/2024/05/my-rare-frameshift-variants-that-escape.html

My Attention Deficit Hyperactivity Disorder in Connection to Variants in Adhesion G Protein-Coupled Receptor Latrophilin (ADGRL aka LPHN) Genes

https://neurodivergence.blogspot.com/2024/06/my-attention-deficit-hyperactivity.html


I learned about some old Dyslexia-linked genes in a 2023 Comorbid ADHD-Dyslexia GWAS study that I made a previous blog post about.  Because of my having Dyslexia and ADHD, I was very interested in the study.

https://neurodivergence.blogspot.com/2024/03/my-potential-comorbid-adhd-dyslexia.html


The following are old Dyslexia-linked genes mentioned in the study:

CMIP, CNTNAP2, CYP19A1, DCDC2, DIP2A, DYX1C1, FOXP2, GCFC2, KIAA0319, KIAA0319L, MRPL19, PCNT, PRMT2, S100B and ROBO1

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10478365/


I looked at variants with condition allele frequencies of no more than 10%.

They are based on Grpmax Filtering AF in gnomAD v4

This annotation can be used for filtering variants by allele frequency against a disease-specific threshold that can be set for each disease (e.g. BA1 in the 2015 ACMG/AMP guidelines). In this case the filtering allele frequency (FAF) is the maximum credible genetic ancestry group AF (e.g. the lower bound of the 95% confidence interval (CI)). If the FAF is above the disease-specific threshold, then the observed AC is not compatible with pathogenicity. See http://cardiodb.org/allelefrequencyapp/ and Whiffin et al. 2017 for additional information. https://gnomad.broadinstitute.org/help/faf

I looked for variants with Combined Annotation Dependent Depletion (CADD) scores of at least 10, and so the variants are predicted to be in the top 10% of the most deleterious. 


This is the snapshot of my Dante Labs account with my genome number 




My Sequencing Genomic Data




My Dante Labs Genomic Data



I have two CNTNAP2 variants, three ROBO1 variants, on FOXP2 variant, one DCDC2 variant, and one FOXP2 variant.

My FOXP2 variant is a Missense variant but also has transcripts that involve 3 Prime Untranslated region.  It involves both coding and regulation.   This variant is extremely rare with it found in only 2 out of 1,613,666 human genomes examined.  FOXP2 is a gene that has connections with Dyslexia, ADHD, Autism, Speech/Language Disorders, Developmental Coordination Disorder, and Schizophrenia.  My FOXP2 Missense has a Combined Annotation Dependent Depletion (CADD) score of 25.0, but there are other In-Silico Predictors that total for an overall prediction of this variant being Benign. This medium impact coding region variant is not Pathogenic.  Therefore, the variant was not included in my blog post about my rare single nucleotide variants that are shown to be potentially Pathogenic according to In-Silico Predictors.  This variant could be a factor in common neurodivergence if considering a polygenic cause that include many common risk factors, and many variants considered in common neurodivergence are actually common variants in noncoding regions with low CADD scores. The rare variants in coding regions of genes associated with the nervous system are often found linked to Autism, Psychotic Disorders, Intellectual Disability, and Neurological Diseases. 

One of my ROBO1 variants is a 3 Prime Untranslated variant, and so it involves regulation.  This gene is connected to Reading Disorder and Dyslexia.   One of the ROBO1 variants that is an intronic variant with a Combined Annotation Dependent Depletion (CADD) score of 20.4 which is a very high score for an intronic variant. 

The DCDC2 variant is the only listed variant that is an insertion-deletion variant, and it involves deletion of over 70 base pairs.  DCDC2 is connected to Dyslexia and Deafness, and so it seems to be connected to auditory processing difficulties.

CNTNAP2 is one of the top 20 genes listed in a 2023 Comorbid ADHD-Dyslexia GWAS study.  It also has connections with Autism. 


FOXP2

FOXP2 (Forkhead Box P2) is a Protein Coding gene. Diseases associated with FOXP2 include Isolated Childhood Apraxia Of Speech and Speech And Communication Disorders. Among its related pathways are Pathways affected in adenoid cystic carcinoma and Wnt / Hedgehog / Notch. Gene Ontology (GO) annotations related to this gene include DNA-binding transcription factor activity and sequence-specific DNA binding. An important paralog of this gene is FOXP4.

 This gene encodes a member of the forkhead/winged-helix (FOX) family of transcription factors. It is expressed in fetal and adult brain as well as in several other organs such as the lung and gut. The protein product contains a FOX DNA-binding domain and a large polyglutamine tract and is an evolutionarily conserved transcription factor, which may bind directly to approximately 300 to 400 gene promoters in the human genome to regulate the expression of a variety of genes. This gene is required for proper development of speech and language regions of the brain during embryogenesis, and may be involved in a variety of biological pathways and cascades that may ultimately influence language development. Mutations in this gene cause speech-language disorder 1 (SPCH1), also known as autosomal dominant speech and language disorder with orofacial dyspraxia. Multiple alternative transcripts encoding different isoforms have been identified in this gene.[provided by RefSeq, Feb 2010]

https://www.genecards.org/cgi-bin/carddisp.pl?gene=FOXP2

rs940890058  7-114642502-G-A     data not available for my mother

Missense variant, 3'UTR 

2 out of 1,613,666 (0.0001239%) Condition allele frequency is 0.000444%

25.0

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA164868669



CNTNAP2

CNTNAP2 (Contactin Associated Protein 2) is a Protein Coding gene. Diseases associated with CNTNAP2 include Pitt-Hopkins-Like Syndrome 1 and Autism 15. Among its related pathways are Primary ovarian insufficiency and Neuroscience. Gene Ontology (GO) annotations related to this gene include enzyme binding. An important paralog of this gene is CNTNAP5.

This gene encodes a member of the neurexin family which functions in the vertebrate nervous system as cell adhesion molecules and receptors. This protein, like other neurexin proteins, contains epidermal growth factor repeats and laminin G domains. In addition, it includes an F5/8 type C domain, discoidin/neuropilin- and fibrinogen-like domains, thrombospondin N-terminal-like domains and a putative PDZ binding site. This protein is localized at the juxtaparanodes of myelinated axons, and mediates interactions between neurons and glia during nervous system development and is also involved in localization of potassium channels within differentiating axons. This gene encompasses almost 1.5% of chromosome 7 and is one of the largest genes in the human genome. It is directly bound and regulated by forkhead box protein P2, a transcription factor related to speech and language development. This gene has been implicated in multiple neurodevelopmental disorders, including Gilles de la Tourette syndrome, schizophrenia, epilepsy, autism, ADHD and intellectual disability. [provided by RefSeq, Jul 2017]

https://www.genecards.org/cgi-bin/carddisp.pl?gene=CNTNAP2

rs115191080  7-147625958-A-T    data not available for my mother         

Intronic variant

3,083 out of 152,260 (2.025%) Condition allele frequency is 6.805%

14.5

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA168752628

rs142189161 7-146676930-A-G   data not available for my mother   

Intronic variant

1,793 out of 152,264 (1.178%) Disease allele frequency is 3.413%

13.7

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA168631938



ROBO1

ROBO1 (Roundabout Guidance Receptor 1) is a Protein Coding gene. Diseases associated with ROBO1 include Neurooculorenal Syndrome and Nystagmus 8, Congenital, Autosomal Recessive. Among its related pathways are Nervous system development and Regulation of expression of SLITs and ROBOs. Gene Ontology (GO) annotations related to this gene include identical protein binding and LRR domain binding. An important paralog of this gene is ROBO2.

 Bilateral symmetric nervous systems have special midline structures that establish a partition between the two mirror image halves. Some axons project toward and across the midline in response to long-range chemoattractants emanating from the midline. The product of this gene is a member of the immunoglobulin gene superfamily and encodes an integral membrane protein that functions in axon guidance and neuronal precursor cell migration. This receptor is activated by SLIT-family proteins, resulting in a repulsive effect on glioma cell guidance in the developing brain. A related gene is located at an adjacent region on chromosome 3. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

https://www.genecards.org/cgi-bin/carddisp.pl?gene=ROBO1

 rs114036696  3-78792211-G-C    data not available for my mother              

Intronic variant

1,064 out of 152,282 (0.6987%) Condition allele frequency is 2.138%

20.4

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA77674799

rs75945484  3-78597554-A-C     data not available for my mother

3'UTR variant

2,916 out of 152,246 (1.915%) Condition allele frequency is 6.387%

14.3

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA77655730

rs147334428  3-79619750-A-T   data not available for my mother

Intronic variant

1,641 out of 152,282 (1.078%) Condition allele frequency is 3.662%

10.9

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA77879477



DCDC2

DCDC2 (Doublecortin Domain Containing 2) is a Protein Coding gene. Diseases associated with DCDC2 include Sclerosing Cholangitis, Neonatal and Deafness, Autosomal Recessive 66. Among its related pathways are Bardet-Biedl syndrome and Ciliopathies. An important paralog of this gene is DCDC2B.

This gene encodes a doublecortin domain-containing family member. The doublecortin domain has been demonstrated to bind tubulin and enhance microtubule polymerization. This family member is thought to function in neuronal migration where it may affect the signaling of primary cilia. Mutations in this gene have been associated with reading disability (RD) type 2, also referred to as developmental dyslexia. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [ provided by RefSeq, Jan 2013]

https://www.genecards.org/cgi-bin/carddisp.pl?gene=DCDC2

rs1561881965  6-24185666- GTTTTACACCCATCCATACACATACACACACACACACACACACACACACACACACACACACATATACACACAGATAAAA-G    78 base pair deletion     data not available for my mother 

Intronic variant        

1,800 out of 148,568 (1.212%) Condition allele frequency is 2.711%

13.1

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA566221504
















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