I am not just a neurodivergent with Dyslexia, Dyspraxia, ADHD. My neurological make include both Neurodivergence and Ataxia. Ataxia is defined as the inability to generate coordinated voluntary movement, which can manifest clinically with signs and symptoms such as clumsiness, nystagmus, dysmetria, abnormal or unsteady gait, dysdiadochokinesis, or dyssynergia. It's a rare neurological problem. The prevalence rate for hereditary ataxias is 10 cases per 100,000 individuals. The prevalence rate for childhood ataxias is 26 cases per 100,000 children.

I noticed Ataxia listed on my Veteran Affairs (VA) Problem List. I thought my coordination problems were connected to Dyspraxia which is a common neurodivergent condition that commonly occurs with Dyslexia and Attention Deficit-Hyperactivity Disorder which are other neurodivergent conditions that I have. I had noticeable coordination problems in early childhood which led to neurological testing being done on me, and so I have history of ataxia in childhood. My mother told me that my father had problems with coordination like I have, and so it seems that I inherited from him. He also had problems with speech, auditory processing, and learning like I have. Unlike me, he had problems with perceiving and understanding emotional cues which make me suspect that he was on the Autistic Spectrum. He was also a highly sensitive person like my mother and me. My paternal Aunt Carrie told me that my father was hyperactive. I inherited my neurodivergence from both my parents.

I have other coordination issues that are listed on my VA Problem List. They are Saccadic Eye Movement deficiencies and Smooth Pursuit movement deficiencies, and those are all eye coordination issues. Dr Harold Levinson's testing included testing my saccadic and smooth pursuit movements, and I was found to be abnormal on both of them. He also tested my optokinetic kinetic eye movement, and I was found to be abnormal on it. The VA neurologists and Dr. Levinson recorded that I had dysdiadochokinesis. The VA psychoneurologist noted that my speech is mildly Dysarthric. I have a soft, high pitched voice.

The VA neurologists recorded that I had abnormal cerebellar system that included

Nystagamus optokinetic with slowed saccades but symmetric horizontal vertically difficulty initiating saccades to command and read.

Dysdiadochokinesia present symmetrically all 4 extremities.

Ataxia on target finger-nose but dysmetria with moving target showing slowed saccadic movements.

Gait with mild ataxia

The VA neurologists confirmed my Dyslexia and Dyspraxia, and they noted that it was genetic and not acquired for I had no progression of symptoms. My VA Problems list include Dyslexia and Abnormal Auditory Perception. I had early therapies in childhood that included auditory therapy, speech therapy, phonics training, and motor skills therapy. I was in special education in my early elementary school years, and I was even mistakenly identified as having an intellectual disability which led to mother getting her Fallopian Tubes tied because she thought that I would need a lot of attention and care. Dr. Levinson diagnosed me as having Cerebellar-Vestibular Dysfunction which he claims is the root of Dyslexia and other neurodivergent conditions which he refers as being all part of Dyslexic Syndrome. The truth is that my coordination problems aren't from just dyspraxia alone. They're also from Ataxia. I can relate to the Dyspraxia because of the difficulty with coordination, planning, learning movements, problems processing a sequence of actions/following multi-step instructions, poor working/short term memory, poor organization, but there is strong overlap and co-morbidity with Dyslexia and ADHD. There is also strong overlap with autism. A lot of people with Dyspraxia have Aspergers Syndrome. I don't have social interaction impairments,and so I am not autistic. The Veteran Affairs neurologists noted that during their examination of me.

I felt that I had to set the record straight that my neurological processing issues aren't just from neurodivergent conditions but from serious cerebellar problems that had been addressed in early childhood but never went away. They became mild and subtle as the result of early childhood therapies. The problems were always present but misunderstood which led to wrong judgments about me by others and myself as well as psychiatric misdiagnoses. I want to help raise awareness and understanding of people with ataxia and that there are neurodivergents that have ataxia.

My neuropsychological testing and neurological testing 2004-2006

Psychologist Dr. McMahon in 2004, Dr. Levinson in 2005, Veteran Affairs Neurologists and Neuropsychologist in 2006

https://neurodivergence.blogspot.com/2021/01/my-neurodivergence-testing.html

Information about Ataxia

https://www.americanbrainfoundation.org/diseases/ataxia/

https://www.sciencedirect.com/science/article/abs/pii/S1751722219301738

https://www.ataxia.org/what-is-ataxia/

https://www.childrens.com/specialties-services/conditions/ataxia

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347818/

My VA Problem List

My possible genetic indicators for Ataxia

I have done whole genome testing through Dante Labs and Sequencing. I have developed a very strong interest in Genomics/Genetics including especially Neurogenetics and genomic studies of neurodivergent conditions.

Considering only my rare variants with allele frequences of no more 0.02%, genes in connection to my Ataxia: SGSM2, IFT172, MC4R, SLC4A2, TMEM63A, TRPM8, CEP290, CYLD, PES1.

I inherited the MC4R, TMEM63A, SLC4A2, CEP290, and PES1 variants from my mother.

There is insufficient data for my mother to see if any other variants are inherited from her.

I never knew my father who has been dead since 1993, and so I have no way of knowing what variants that I inherited from him.

I considered only predicted deleterious variants that have an allele frequency of no more than 0.02% which is the estimated frequency of childhood ataxia and CADD scores of at least 20 which is in the top 1% of most deleterious variants.

I looked at variants in genes that have ataxia as human phenotype and/or expression in cerebellar system

I included Human phenotypes that have to do with both neurological disorders and psychiatric disorders. There is a strong overlap between them that needs to be considered. My own neurological problems were undetected by mental health professionals throughout my life with me having very little understanding of myself. The Navy doctors and psychologist didn't know what was really going on with me.

https://useast.ensembl.org/info/genome/variation/prediction/predicted_data.html

What is Combined Annotation Dependent Depletion (CADD)?

CADD is a tool for scoring the deleteriousness of single nucleotide variants as well as insertion/deletions variants in the human genome.

While many variant annotation and scoring tools are around, most annotations tend to exploit a single information type (e.g. conservation) and/or are restricted in scope (e.g. to missense changes). Thus, a broadly applicable metric that objectively weights and integrates diverse information is needed. Combined Annotation Dependent Depletion (CADD) is a framework that integrates multiple annotations into one metric by contrasting variants that survived natural selection with simulated mutations.

C-scores strongly correlate with allelic diversity, pathogenicity of both coding and non-coding variants, and experimentally measured regulatory effects, and also highly rank causal variants within individual genome sequences. Finally, C-scores of complex trait-associated variants from genome-wide association studies (GWAS) are significantly higher than matched controls and correlate with study sample size, likely reflecting the increased accuracy of larger GWAS.

CADD can quantitatively prioritize functional, deleterious, and disease causal variants across a wide range of functional categories, effect sizes and genetic architectures and can be used prioritize causal variation in both research and clinical settings.

In addition to this website, CADD has been described in three publications. The most recent manuscript describes CADD-Splice (CADD v1.6), the latest extension of CADD to improve its predictions of splicing effects:

https://cadd.gs.washington.edu/

What are the scores in the files and which score cutoff should I use?

The last column of the provided files is the PHRED-like (-10*log10(rank/total)) scaled C-score ranking a variant relative to all possible substitutions of the human genome (8.6x10^9). Like explained above, a scaled C-score of greater of equal 10 indicates that these are predicted to be the 10% most deleterious substitutions that you can do to the human genome, a score of greater or equal 20 indicates the 1% most deleterious and so on.

The second to last column is the raw score of the model. Due to the high mislabeling in our training data, it does not have any interpretation (even the sign does not have an interpretation). The higher the raw C score the more predicted to be deleterious. If you want to do a non-parametric test between sets of variants, we recommend using this raw C-score (see above). If you want to put a cutoff on deleteriousness, we recommend the last column (scaled C-score) as it has some interpretation by relating the raw C-score to the raw C-scores of all possible substitutions in the human genome.

If you would like to apply a cutoff on deleteriousness, e.g. to identify potentially pathogenic variants, we would suggest to put a cutoff somewhere between 10 and 20. Maybe at 15, as this also happens to be the median value for all possible canonical splice site changes and non-synonymous variants in CADD v1.0. However, there is not a natural choice here -- it is always arbitrary. We therefore recommend integrating C-scores with other evidence and to rank your candidates for follow up rather than hard filtering.

https://cadd.gs.washington.edu/info

I checked for Single Nucleotide Variants with an allele frequency of no more than 0.02%, predicted to be deleterious according to DANN in Enlis Genome Personal, and have CADD scores of at least 20. My Dante Labs genomic data is in Enlis Genome Personal. I checked to see if the variants also appeared in my Sequencing genomic data in Genome Explorer. Dante Labs genome can have variants that Sequencing don't have and vice versa.

I checked them in Varsome, and I disqualified any that have any predictions of being Benign/Likely Benign, Tolerated.

One is a Stop Gained. Two are Missense. One is a Splice Acceptor. Stop Gained and Splice Acceptor are High Impact variants that can lead to loss of function.

Stop Gained - A sequence variant whereby at least one base of a codon is changed, resulting in a premature stop codon, leading to a shortened polypeptide.

http://www.sequenceontology.org/browser/current_svn/term/SO:0001587

https://en.wikipedia.org/wiki/Nonsense_mutation

Splice Acceptor - A splice variant that changes the 2 base region at the 3' end of an intron.

http://www.sequenceontology.org/browser/current_svn/term/SO:0001574

https://en.wikipedia.org/wiki/Splice_site_mutation

https://www.enlis.com/blog/page/2/

Summary: Annotating genetic variants, especially non-coding variants, for the purpose of identifying pathogenic variants remains a challenge. Combined annotation-dependent depletion (CADD) is an algorithm designed to annotate both coding and non-coding variants, and has been shown to outperform other annotation algorithms. CADD trains a linear kernel support vector machine (SVM) to differentiate evolutionarily derived, likely benign, alleles from simulated, likely deleterious, variants. However, SVMs cannot capture non-linear relationships among the features, which can limit performance. To address this issue, we have developed DANN. DANN uses the same feature set and training data as CADD to train a deep neural network (DNN). DNNs can capture non-linear relationships among features and are better suited than SVMs for problems with a large number of samples and features. We exploit Compute Unified Device Architecture-compatible graphics processing units and deep learning techniques such as dropout and momentum training to accelerate the DNN training. DANN achieves about a 19% relative reduction in the error rate and about a 14% relative increase in the area under the curve (AUC) metric over CADD’s SVM methodology.

https://academic.oup.com/bioinformatics/article/31/5/761/2748191

Meta scores: These predictors determine a pathogenicity based on the combined evidence from multiple other in-silico predictors. Note: Engines are assigned a prediction points score based on the strength of the calibrated prediction. Supporting: 1 point. Moderate: 2 points. Strong: 4 points. Very Strong: 8 points.

BayesDel addAF

A deleteriousness prediction meta-score for SNVs and indels with inclusion of MaxAF. See https://doi.org/10.1002/humu.23158 for details. The range of the score in dbNSFP is from -1.11707 to 0.750927. The higher the score, the more likely the variant is pathogenic. The author suggested cutoff between deleterious ('D') and tolerated ('T') is 0.0692655.

BayesDel noAF

A deleteriousness prediction meta-score for SNVs and indels without inclusion of MaxAF. See https://doi.org/10.1002/humu.23158 for details. The range of the score in dbNSFP is from -1.31914 to 0.840878. The higher the score, the more likely the variant is pathogenic. The author suggested cutoff between deleterious ('D') and tolerated ('T') is -0.0570105.

REVEL

The Rare Exome Variant Ensemble Learner REVEL is an ensemble method for predicting the pathogenicity of missense variants. It integrates scores from MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. Score range from 0 to 1 and variants with higher scores are predicted to be more likely to be pathogenic.

REVEL does not provide a descriptive prediction but for convenience, we display scores above 0.5, as 'likely disease causing' and display scores below 0.5 as 'likely benign'. It was estimated that 75.4% of disease mutations but only 10.9% of neutral variants have a score above 0.5

We strongly recommend the actual score is used when assessing a variant and a cut-off appropriate to your requirements is chosen.

MetaLR

MetaLR is an ensemble score using Logistic Regression (LR) to integrate nine prediction scores (SIFT, PolyPhen-2, GERP++, MutationTaster, Mutation Assessor, FATHMM, LRT, SiPhy and PhyloP) and allele frequencies in 1KG database. The tool has been trained on 36,192 SNVs from UniProt. Range 0 to 1.

MetaRNN

Our recurrent neural network (RNN) based ensemble prediction score, which incorporated 16 scores (SIFT, Polyphen2_HDIV, Polyphen2_HVAR, MutationAssessor, PROVEAN, VEST4, M-CAP, REVEL, MutPred, MVP, PrimateAI, DEOGEN2, CADD, fathmm-XF, Eigen and GenoCanyon), 8 conservation scores (GERP, phyloP100way_vertebrate, phyloP30way_mammalian, phyloP17way_primate, phastCons100way_vertebrate, phastCons30way_mammalian, phastCons17way_primate and SiPhy), and allele frequency information from the 1000 Genomes Project (1000GP), ExAC, and gnomAD. Larger value means the SNV is more likely to be damaging. Scores range from 0 to 1.

MetaSVM

MetaSVM is an ensemble score using Support Vector Machine (SVM) to integrate nine prediction scores (SIFT, PolyPhen-2, GERP++, MutationTaster, Mutation Assessor, FATHMM, LRT, SiPhy and PhyloP) and allele frequencies in 1KG database. The tool has been trained on 36,192 SNVs from UniProt. Range -2.0058 to +3.0399.

rs867998099 C/T no data available for my mother

Stop Gained

SGSM2

3 out of 1,614,054 (0.0001859%)

DANN: 0.9978386290023271

CADD: 40.0

Metascore 8 Pathogenic very strong

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA286906028

https://gnomad.broadinstitute.org/variant/17-2379146-C-T?dataset=gnomad_r4

https://varsome.com/variant/hg38/rs867998099?annotation-mode=germline

Human Phenotypes: Progressive cerebellar ataxia, Depression, Depression, Poor eye contact, Postural instability, Impaired social interactions, Abnormal social behavior, Dysdiadochokinesis, Broad-based gait, Insomnia, Gaze-evoked nystagmus, Anxiety, Impaired smooth pursuit, Dysmetric saccades, Dysmetria, Truncal ataxia, Spastic gait, Agitation, Abnormality of ocular smooth pursuit, Intention tremor, Hyperacusis

https://maayanlab.cloud/archs4/gene/SGSM2

rs52804924 G/T my mother has it too

Missense

MC4R

34 out of 1,605,580 (0.002107%)

DANN: 0.9966255349609099

CADD: 27.9

PP3: Pathogenic Strong

Metascore 20 Pathogenic very strong

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA214149

https://gnomad.broadinstitute.org/variant/18-60371454-G-T?dataset=gnomad_r4

Reported Pathogenic, Likely Pathogenic for Obesity in Clinvar

https://www.ncbi.nlm.nih.gov/clinvar/variation/36488/

https://varsome.com/variant/hg38/rs52804924?annotation-mode=germline

Human Phenotypes: Visual hallucinations, Delayed gross motor development, Agitation, Progressive cerebellar ataxia, Anxiety, Broad-based gait, Truncal ataxia, Dysdiadochokinesis, Psychosis, Dysmetria, Impaired smooth pursuit, Gait imbalance, Depression, Restlessness, Action tremor, Delusions, Specific learning disability, Impaired social interactions, Abnormal social behavior, Abnormality of pain sensation, Abnormality of ocular pursuit, Postural instability, Poor eye contact

https://maayanlab.cloud/archs4/gene/MC4R

rs976552782 C/A no data available for my mother

Missense

IFT172

7 out of 1,613,130 (0.0004339%)

DANN: 0.9981074046322775

CADD: 26.6

PP3: Pathogenic Moderate

Metascore 14 Pathogenic very strong

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA44515401

https://gnomad.broadinstitute.org/variant/2-27480144-C-A?dataset=gnomad_r4

https://varsome.com/variant/hg38/rs976552782?annotation-mode=germline

Human Phenotypes: Gait imbalance, Dysmetric saccades, Postural instability, Gaze-evoked nystagmus, Abnormality of ocular smooth pursuit, Action tremor, Hyperacusis, Progressive cerebellar ataxia, Insomnia, Poor coordination, Visual hallucinations, Impaired smooth pursuit, Dysdiadochokinesis, Abnormality of saccadic eye movements, Depression, Oculomotor apraxia

https://maayanlab.cloud/archs4/gene/IFT172

rs746816423 7-151072063-G-A my mother has it too

Missense

SLC4A2

23 out of 1,613,906 (0.0014125%)

DANN: 0.9995332606326633

CADD: 28.2

Reported in ClinVar as Uncertain Significance for Inborn Genetic Diseases

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA4571399

https://gnomad.broadinstitute.org/variant/7-151072063-G-A?dataset=gnomad_r4

https://varsome.com/variant/hg38/rs746816423?annotation-mode=germline

PP3 Pathogenic

8 Pathogenic Very Strong, 2 Uncertain

rs966645435 C/G my mother has it too

Splice Acceptor

TMEM63A

18 out of 1,614,038 (0.001115%)

DANN: 0.9940434013774456

CADD: 32.0

Metascore 3 Pathogenic moderate

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA38540925

https://gnomad.broadinstitute.org/variant/1-225867164-C-G?dataset=gnomad_r4

https://varsome.com/variant/hg38/rs966645435?annotation-mode=germline

Human Phenotypes: Ataxia, Dysmetria, Specific learning disability, Intention tremor, Delayed gross motor development, Abnormality of movement, Tremor, Abnormality of coordination, Tremor, Motor delay, Abnormality of the nervous system, Abnormal central motor function, Action tremor, Abnormality of eye movement, Neurodevelopmental abnormality, Neurodevelopmental delay, Abnormal nervous system physiology, Kinetic tremor, Nystagamus

https://www.genecards.org/cgi-bin/carddisp.pl?gene=TMEM63A

Intention tremor, Abnormal auditory evoked potentials, Slow saccadic eye movements, Spastic gait, Dysmetria, Clumsiness

https://maayanlab.cloud/archs4/gene/TMEM63A

I also checked for Insertion, Deletions with a frequency of no more than 0.02% with CADD scores of at least 25. DANN scores and Varsome information are unavailable for insertions and deletions.

All of them are Frameshifts which are High Impact variants that can lead to loss of function.

Frameshift variant - A sequence variant which causes a disruption of the translational reading frame, because the number of nucleotides inserted or deleted is not a multiple of three.

http://www.sequenceontology.org/browser/current_svn/term/SO:0001589

https://en.wikipedia.org/wiki/Frameshift_mutation

rsID: rs761976363 Insertion data unavailable for my mother

Type: Frameshift

Gene: TRPM8

Allele Frequency: 11 out of 1,599,978 (0.0006875%)

CADD Score: 33.0

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2182690

https://gnomad.broadinstitute.org/variant/2-233980248-C-CT?dataset=gnomad_r4

Human Phenotypes: Gaze-evoked nystagmus, Action tremor, Dysmetric saccades, Dysdiadochokinesis, Impaired smooth pursuit, Spastic gait, Broad-based gait, Clumsiness, Impaired proprioception, Abnormality of the vocal cords, Abnormality of ocular smooth pursuit, Visual hallucinations, Dysmetria, Scanning speech, Anxiety, Truncal ataxia, Progressive cerebellar ataxia

https://maayanlab.cloud/archs4/gene/TRPM8

rs757255407 Insertion my mother has it too

Frameshift

CEP290

48 out of 1,608,484 (0.002984%)

CADD: 27.5

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA6711277

https://gnomad.broadinstitute.org/variant/12-88049231-C-CTG?dataset=gnomad_r4

Human Phenotypes: Ataxia, Atypical behavior, Autistic behavior, Aggressive behavior, Oculomotor apraxia, Nystagamus, Abnormality of the nervous system, Abnormality of higher mental function, Abnormality of coordination, Abnormality of central motor function, Apraxia, Abnormality of eye movement, Abnormal aggressive,impulsive,or violent behavior, Neurodevelopmental abnormality, Neurodevelopmental delay, Abnormal nervous system physiology, Abnormal autonomic nervous system physiology, Hearing abnormality, Abnormality of the peripheral nervous system, Abnormal emotion/affect behavior, Abnormal ear physiology

text mining disease associations include Apraxia, Episodic Ataxia

https://www.genecards.org/cgi-bin/carddisp.pl?gene=CEP290

Human Phenotypes: Photophobia, Gait imbalance, Broad-based gait, Poor coordination, Specific learning disability, Progressive cerebellar ataxia, Gaze-evoked nystagmus, Oculomotor apraxia

https://maayanlab.cloud/archs4/gene/CEP290

CEP290 is a strong candidate gene for autism

https://gene.sfari.org/database/human-gene/CEP290

I also checked for variants in 5 Prime Untranslated Regions which regulate RNA stability, translation and trafficking. Variants in Untranslated Regions have potentially large impact. Untranslated regions regulate known genes. They predict known function elements. Some 5'UTRs have upstream Open Reading Frames (uORFs) which are upstream of 49% of all genes and lead to 30 - 80% reduction in protein levels. uAUG-creating variants are under strong negative selection in population, more deleterious if overlapping coding sequence, and can cause loss of function and severe disease.

I considered only the 5'UTR variants that have predicted consequence uAUG Gained, uAUG Lost, uStop Gained, uStop Lost, uFrameshift.

https://en.wikipedia.org/wiki/Five_prime_untranslated_region

The 5′ untranslated region is the mRNA domain that contains plenty of elements such as upstream ORFs (uORFs), internal ribosome entry sites, microRNA binding sites, and structural components involved in the regulation of mRNA stability, pre-mRNA splicing, and translation initiation. Deregulation of cis-regulatory elements or secondary structures within the 5′UTRs may cause a change in gene expression [1]. This shows the functional importance of 5′UTR in control of gene expression. Furthermore, a growing number of evidence demonstrates that mutations within 5′UTRs are often linked with diseases, including cancer [2,3,4]. Oncogenes and tumor suppressors require precise regulation and often express transcripts containing various and atypically long 5′ untranslated regions with new regulatory elements, such as uORFs or secondary structures [5,6]. Moreover, extension of 5′ UTR due to the use of an alternative promoter may lead to an overlap with a gene located on the opposite DNA strand. Such overlap at 5’ ends may be associated with additional regulatory functions [7,8]. This review summarizes the roles of 5’UTRs and the regulatory mechanisms in which these sequences are involved.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9917990/

https://academic.oup.com/bioinformatics/article/37/8/1171/5905476?login=false

rs1020043545 G/T data unavailable for my mother

uAUG Gained (Premature Start Codon Gain)

CYLD

8 out of 152,490 (0.005246%)

21.4

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA281292618

https://gnomad.broadinstitute.org/variant/16-50742094-G-T?dataset=gnomad_r4

Human Phenotypes: Visual hallucinations, Action tremor, Gaze-evoked nystagmus, Poor eye contact, Progressive cerebellar ataxia, Broad-based gait, Scanning speech, Truncal ataxia, Dysmetria, Depression, Anxiety, Dysdiadochokinesis, Impaired social interactions, Abnormal social behavior, Impaired smooth pursuit, Postural instability, Intention tremor, Dysmetric saccades, Spastic gait, Abnormality of ocular smooth pursuit, Abnormality of saccadic eye movements, Inappropriate behavior, Slow saccadic eye movements

https://maayanlab.cloud/archs4/gene/CYLD