This is a post about my IQSEC1 variants which are possible genetic indicators for my Dyspraxia which is also known as Developmental Coordination Disorder based on the Genome-Wide Association Study of Motor Coordination. I also have Dyslexia and ADHD. The Dyspraxia and Dyslexia were treated with auditory therapy, speech therapy, phonics training, and motor skills therapy. The IQSEC1 variants could also be possible genetic indicators for my Dyslexia and ADHD.
My Neurodivergence Testing
My Speech Milestones
Parental Questionnaire that my mother did in regards to my neurodivergence
Genome-Wide Association Study of Motor Coordination
Abstract
The ability to finely control our movement is key to achieving many of the educational milestones and life-skills we develop throughout our lives. Despite the centrality of coordination to early development, there is a vast gap in our understanding of the underlying biology. Like most complex traits, both genetics and environment influence motor coordination, however, the specific genes, early environmental risk factors and molecular pathways are unknown. Previous studies have shown that about 5% of school-age children experience unexplained difficulties with motor coordination. These children are said to have Developmental Coordination Disorder (DCD). For children with DCD, these motor coordination difficulties significantly impact their everyday life and learning. DCD is associated with poorer academic achievement, reduced quality of life, it can constrain career opportunities and increase the risk of mental health issues in adulthood. Despite the high prevalence of coordination difficulties, many children remain undiagnosed by healthcare professionals. Compounding under-diagnosis in the clinic, research into the etiology of DCD is severely underrepresented in the literature. Here we present the first genome-wide association study to examine the genetic basis of early motor coordination in the context of motor difficulties. Using data from the Avon Longitudinal Study of Parents and Children we generate a derived measure of motor coordination from four components of the Movement Assessment Battery for Children, providing an overall measure of coordination across the full range of ability. We perform the first genome-wide association analysis focused on motor coordination (N = 4542). No single nucleotide polymorphisms (SNPs) met the threshold for genome-wide significance, however, 59 SNPs showed suggestive associations. Three regions contained multiple suggestively associated SNPs, within five preliminary candidate genes: IQSEC1, LRCC1, SYNJ2B2, ADAM20, and ADAM21. Association to the gene IQSEC1 suggests a potential link to axon guidance and dendritic projection processes as a potential underlying mechanism of motor coordination difficulties. This represents an interesting potential mechanism, and whilst further validation is essential, it generates a direct window into the biology of motor coordination difficulties. This research has identified potential biological drivers of DCD, a first step towards understanding this common, yet neglected neurodevelopmental disorder.
Keywords: ALSPAC; GWAS; coordination; development; developmental coordination disorder; dyspraxia; motor coordination; neurodevelopment.
https://pubmed.ncbi.nlm.nih.gov/34177493/
https://www.frontiersin.org/articles/10.3389/fnhum.2021.669902/full.
IQSEC1
From Wikipedia, the free encyclopedia
IQ motif and SEC7 domain-containing protein 1 also known as ARF-GEP100 (ADP-Ribosylation Factor - Guanine nucleotide-Exchange Protein - 100-kDa) is a protein that in humans is encoded by the IQSEC1 gene.[5][6]
Function[edit]
The ARF-GEP100 protein is involved in signal transduction. It is a guanine nucleotide exchange factor that promotes binding of GTP to ADP ribosylation factor protein ARF6 and to a lesser extent ARF1 and ARF5.[6] This activates the ADP-ribosylation activity of the target protein and cause it to modify its substrates. ARF-GEP100, through activation of ARF6, is therefore involved in the control of processes such as endocytosis of plasma membrane proteins, E-cadherin recycling and actin cytoskeleton remodeling.[7] ARF-GEP100 appears particularly important in regulating cell adhesion, with reductions in the level of this protein causing enhanced spreading and attachment of cells.[8]
It is highly expressed in the prefrontal cortex, and throughout the rest of the brain, and is believed to have a role in learning and memory, having been detected as phosphorylated in a phospho screen of the PSD.[9]
https://en.wikipedia.org/wiki/IQSEC1
Entrez Gene Summary for IQSEC1 Gene
Predicted to enable protein kinase binding activity. Predicted to be involved in several processes, including positive regulation of focal adhesion disassembly; positive regulation of keratinocyte migration; and regulation of postsynaptic neurotransmitter receptor internalization. Located in nucleolus. Implicated in intellectual developmental disorder with short stature and behavioral abnormalities. [provided by Alliance of Genome Resources, Nov 2021]
Gene Ontology (GO) - Biological Process for IQSEC1 Gene
involved_in actin cytoskeleton organization
involved_in regulation of ARF protein signal transduction
involved_in positive regulation of GTPase activity
involved_in positive regulation of keratinocyte migration
involved_in dendritic spine development
involved_in positive regulation of focal adhesion disassembly
Human phenotypes for IQSEC1 that seem to fit with neurodivergence.
Behavioral abnormality
Abnormality of the nervous system
Depression
Autistic behavior
Short attention span
Delayed speech and language development
Hyperactivity
Abnormality of movement
Abnormal emotion/affect behavior
Abnormality of coordination
Aggressive behavior
Language impairment
Ataxia
Hypotonia
Motor delay
Disinhibition
Gait disturbance
Abnormal nervous system electrophysiology
Neurological speech impairment
Impulsivity
Abnormal eye physiology
Abnormality of higher mental function
Delayed gross motor development
Poor speech
Abnormal aggressive, impulsive or violent behavior
Attention Deficit Hyperactivity Disorder
Neurodevelopmental delay
Neurodevelopmental abnormality
Impairment in personality functioning
Delayed ability to walk
I have the following rare variant which is considered benign which means that it doesn't cause disease. Recessive, rare mutations in IQSEC1 are associated with intellectual developmental disorder with short stature and behavioral abnormalities. Functional studies suggested that the rare pathogenic IQSEC1 variants resulted in defects in axon guidance and dendritic projection processes. Affected family members presented with severe intellectual disability, short stature, speech aphasia and behavioral problems with history of delayed motor milestones. In humans, IQSEC1 belongs to a family of three related genes. Mutations in the other gene family members, IQSEC2 and IQSEC3, previously were implicated in certain types of intellectual disabilities and/or seizures.
Maybe the rare mutation that I have could be associated with defects in axon guidance and dendritic projection processes that include much milder symptoms that include no intellectual disability.
IQSEC1 rs113261173 G/A
Frequency:
A=0.009271 (2454/264690, TOPMED)
A=0.002384 (596/250036, GnomAD_exome)
A=0.008892 (1247/140244, GnomAD)
A=0.003076 (368/119648, ExAC)
A=0.00255 (126/49316, ALFA)
A=0.01076 (140/13006, GO-ESP)
A=0.0100 (50/5008, 1000G)
A=0.005 (1/216, Qatari)
The following variants that I have that have been considered to be possible indicators for Developmental Coordination Disorder
Supplementary Table 1 | Full list of association results for the 59 SNPs that met the threshold for suggestive association (P ≤ 5 × 10–5) on the SumQMS4. The statistical significance for each of the 59 SNPs is also reported for the binary DCD case/control association test.
The first one that I listed is rs62232913 because it's a homozygous variant, and so I inherited one mutant allele from both my parents which gives me a higher chance of having defects in axon guidance and dendritic projection processes than those with heterozygous variant which includes just one mutant allele.
Chromosome 3 IQSEC1 rs62232913 A/A
Frequency:
A=0.204156 (54038/264690, TOPMED)
A=0.210645 (29519/140136, GnomAD)
A=0.21588 (4078/18890, ALFA)
All of the rest of the IQSEC1 variants are heterozygous.
Chromosome 3 IQSEC1 rs11128630 G/T
Frequency:
T=0.163236 (43207/264690, TOPMED)
T=0.202383 (30364/150032, ALFA)
T=0.174071 (24386/140092, GnomAD)
Chromosome 3 IQSEC1 rs11718914 T/C
Frequency:
C=0.166988 (44200/264690, TOPMED)
C=0.176622 (24738/140062, GnomAD)
C=0.18836 (6319/33548, ALFA) (
Chromosome 3 IQSEC1 rs74653607 C/T
Frequency:
T=0.166670 (44116/264690, TOPMED)
T=0.176314 (24704/140114, GnomAD)
T=0.18909 (3572/18890, ALFA)
Chromosome 3 IQSEC1 rs11929559 T/C
Frequency:
C=0.174317 (46140/264690, TOPMED)
C=0.182327 (25525/139996, GnomAD)
C=0.19132 (3614/18890, ALFA)
Chromosome 3 IQSEC1 rs11925501 C/T
Frequency:
T=0.163561 (43293/264690, TOPMED)
T=0.172512 (24142/139944, GnomAD)
T=0.18555 (3505/18890, ALFA)
Chromosome 3 IQSEC1 rs9841637 G/A
Frequency:
A=0.218777 (57908/264690, TOPMED)
A=0.226252 (31702/140118, GnomAD)
A=0.21869 (4131/18890, ALFA)
Chromosome 3 IQSEC1 rs9841967 G/A
Frequency:
A=0.219487 (58096/264690, TOPMED)
A=0.211975 (53854/254058, ALFA)
A=0.227035 (31814/140128, GnomAD)
Chromosome 3 IQSEC1 rs112216455 C/A
Frequency:
A=0.170354 (45091/264690, TOPMED)
A=0.179608 (25171/140144, GnomAD)
A=0.18729 (3538/18890, ALFA)
Chromosome 3 IQSEC1 rs12498047 C/G
Frequency:
G=0.172133 (45562/264690, TOPMED)
G=0.181186 (25399/140182, GnomAD)
G=0.18825 (3556/18890, ALFA)
Chromosome 3 IQSEC1 rs75528281 C/T
Frequency:
T=0.164800 (43621/264690, TOPMED)
T=0.18359 (3077/16760, 8.3KJPN)
T=0.09455 (1434/15166, ALFA)
Chromosome 3 IQSEC1 rs9815898 T/C
Frequency:
C=0.230927 (61124/264690, TOPMED)
C=0.236641 (33142/140052, GnomAD)
C=0.21852 (18241/83474, ALFA)
Chromosome 3 IQSEC1 rs75150723 T/C
Frequency:
C=0.165552 (43820/264690, TOPMED)
C=0.174283 (24425/140146, GnomAD)
C=0.18539 (3502/18890, ALFA)
I also happen to have 2 rare IQSEC2 variants. IQSEC2 is a X Chromosome gene.
Chromosome X IQSEC2 rs376149648 T
T=0.000057 (15/264690, TOPMED)
T=0.000011 (2/180268, GnomAD_exome)
T=0.000010 (1/104706, GnomAD) (- 3 less)
T=0.00001 (1/85025, ExAC)
T=0.00000 (0/14050, ALFA)
T=0.00009 (1/10557, GO-ESP)
Chromosome X rs191862735 G IQSEC2
G=0.009014 (2386/264690, TOPMED)
G=0.009752 (1018/104393, GnomAD)
G=0.01129 (209/18520, ALFA) (- 5 less)
G=0.0021 (8/3775, 1000G)
G=0.0146 (54/3708, TWINSUK)
G=0.0180 (52/2889, ALSPAC)
G=0.03 (1/40, GENOME_DK)
A=0.1 (1/8, SGDP_PRJ)
Entrez Gene Summary for IQSEC2 Gene
This gene encodes a guanine nucleotide exchange factor for the ARF family of small GTP-binding proteins. The encoded protein is a component of the postsynaptic density at excitatory synapses, and may play a critical role in cytoskeletal and synaptic organization through the activation of selected ARF substrates including ARF1 and ARF6. Mutations in this gene have been implicated in nonsyndromic X-linked cognitive disability. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2011]
Gene Ontology (GO) - Biological Process for IQSEC2 Gene
involved_in actin cytoskeleton organization
involved_in regulation of ARF protein signal transduction IEA
involved_in regulation of catalytic activity IEA
involved_in modulation of chemical synaptic transmission IMP 27009485
involved_in regulation of neurotransmitter receptor localization to postsynaptic specialization membrane
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