The day I sent 7 long e-mails

To: Human Genome Sequencing Center (HGSC) at Baylor College of Medicine

Subject: Inquiry Regarding Structural-Genomic Collaboration on a Newly Characterized Motor-Vasomotor Phenotype Cohort

Dear Drs. Sedlazeck, Gibbs, and Reid, and Ms. Muzny,

I hope this note finds you well. I am reaching out to explore whether an initial discussion with the HGSC team might be possible regarding a phenotype we are studying that may intersect with RCCX structural variation, CAH-X–related mechanisms, and associated ECM involvement, as well as autonomic and vascular-tone regulation and ion-channel physiology.

On the clinical side, our sleep-medicine collaborators (Drs. Raffaele Ferri, Giuseppe Lanza, and Oliver Bernath) are characterizing a PSG-defined entity we are referring to as Nocturnal Oscillatory Cyclic Myoclonus (NOCM). NOCM describes recurrent cyclic myoclonic bursts that appear at sleep onset and reemerge at subsequent sleep–wake transitions throughout the night. This motor-based definition is being prepared for submission to the International Classification of Sleep Disorders (ICSD-3-TR). The condition can be highly impactful on sleep stability and daytime functioning, which has motivated our coordinated effort to define its mechanisms.

Within this umbrella, emerging patterns from our initial review of the 55 whole-genome datasets suggest at least two mechanistic subtypes. One reflects ion-channel hyperexcitability, consistent with electrically mediated instability at sleep-stage boundaries. The second is a vasomotor/autonomic subtype, termed Sleep-Onset Oscillatory Vasomotor Myoclonus (SOVM), in which these cyclic bursts appear closely linked to vascular-tone dysregulation, autonomic imbalance, ECM involvement, RAAS-related pathways, and other physiologic factors. This vasomotor subtype appears particularly relevant to the structural-genomic questions we hope to explore.

Our cohort includes 55 individuals who have undergone whole-genome sequencing (VCF and CRAM available), and our larger international community includes more than 3,000 individuals reporting this condition. Across these datasets, we are seeing indications that structural variation within the RCCX module, TNXB/TNXA hybridization, CYP21A2 duplication or hybrid structures, C4A/C4B variation, and RAAS regulatory architecture—including potential ACE structural variation—may contribute to the mechanistic landscape. The overlap between these emerging patterns and the genomic complexities historically described in CAH-X is the reason I am reaching out to your team specifically.

NIH colleagues experienced in CAH-X and RCCX (Dr. Lao and Dr. Merke) are aware of our work. They expressed interest but noted that they do not currently have an active protocol or funding mechanism to extend long-read or RCCX-focused structural analysis beyond their existing CAH cohort. Given this limitation, I am hoping to understand whether HGSC might be open to an exploratory conversation about feasibility, scope, and a possible phased approach.

We are hoping to explore questions such as:

1. Whether HGSC could evaluate structural variation within the RCCX region, including TNXA→TNXB crossover patterns, CYP21A2 hybrid or duplication configurations, and C4A/C4B copy-number architecture, beginning with a small subset of priority samples.

2. Whether ACE structural variation and related RAAS-regulatory patterns could be investigated using long-read sequencing or other approaches, given their potential relevance to the vasomotor/autonomic subtype.

3. Whether the 55 whole-genome datasets could be reviewed for recurrent patterns across ion-channel and ECM gene domains to help refine mechanistic subtyping within NOCM.

4. Whether insights from an initial subset might help guide a broader structural-variant analysis and support integration of genotype and phenotype in collaboration with our clinical sleep team.

If an exploratory call is possible, I would greatly appreciate the opportunity to learn what might be feasible within HGSC’s research framework and what considerations would guide next steps. If appropriate, I would also be glad to keep our NIH colleagues informed as structural findings develop.

Thank you very much for your time and consideration.

I would be grateful for any guidance on whether a brief initial meeting with the appropriate members of your team might be arranged.

Sincerely,

Tracy

Founder, SOVM Collaborative

www.HypnicJerking.com

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To: Laura Lewis, Lewis Lab @ MIT

Subject: Neurovascular Dynamics at Sleep Onset – Potential Overlap with New NOCM Phenotype

Dear Dr. Lewis,

I hope this note finds you well. I recently read your comments in the Smithsonian article on neural dynamics at the wake–sleep boundary, and it prompted me to reach out because the transition phenomena you describe align closely with a phenotype I’ve been coordinating research on internationally.

Over the past year, I’ve been working with a team of sleep researchers (Drs. Raffaele Ferri, Giuseppe Lanza, and Oliver Bernath) to characterize a motor–autonomic transition disorder now being prepared for ICSD-3-TR consideration under the name Nocturnal Oscillatory Cyclic Myoclonus (NOCM). The core signature occurs at the N1–N2 boundary and appears to reflect a misalignment between neural oscillatory shifts and vascular or CSF-related tone regulation, which overlaps with the neurovascular transitions your lab has described.

Across our cohort, a large subset of individuals show a high polygenic burden of ion-channel variants (calcium, sodium, sodium, potassium), and structural or ECM-related signals in the RCCX/TNXB region. Both patterns could feasibly affect neurovascular coupling. Clinically, symptoms consistently improve when structural load is reduced (atlas adjustment, styloidectomy, herniation repair), which suggests that impaired vascular–mechanical synchrony at sleep onset may be a key component of the phenotype.

Given your work on electrophysiological–hemodynamic synchrony, CSF pulsatility, and neurovascular dynamics during sleep transitions, I wondered whether a brief conversation might be of interest. I would be happy to share a concise summary or some of our case reviews.

Thank you so much for considering this, and for the clarity your work has brought to this area.

Thank you so much,

Tracy Hans

hypnicjerking.com