Genetics Aug 20, 2019

RCCX Theory in brief:

  • Co-inherited gene mutations of the RCCX module may explain presence of clusters of genetic illness in families and individuals involving hypermobility/fibrosis (TNXB gene), chronic medical illness (CYP21A2 gene, i.e. EDS-HT, CFS/ME, FM, POTS, MCAS, etc.), psychiatric illness (CYP21A2 gene) and autoimmune diseases (C4 gene)
  • CYP21A2 gene mutations could confer a stress vulnerability for the development of chronic medical illness (EDS-HT, CFS/ME, FM, POTS, MCAS, etc.) via "21hydroxylase overwhelm" and via PTSD-wiring from CAPS (CYP21A2 Mutation Associated Neuropsychiatric Spectrum) plus negative events which predisposes to 80% of the major psychiatric illnesses (anxiety disorders, mood disorders, attention disorders, autism spectrum).
  • Both "21-hydroxylase overwhelm" and PTSD wiring associated with CAPS could turn cause stress-induced mitochondrial shutdown

CYP21A2 is well known for its role in disease, most known being Congenital Adrenal Hyperplasia (CAH),  which is usually a result of more severe CYP21A2 mutations which have hormonal and salt-wasting implications meaning it usually gets diagnosed early in life.

On a bit of digging into my own genetics I discovered a CYP21A2 mutation with a known implication in NCAH. (Non-classical CAH)

(CYP21A2):c.188A>T (p.His63Leu), (Frequency 12%)

Inhibition of CYP21A2 Enzyme Activity Caused by Novel Missense Mutations Identified in Brazilian and Scandinavian Patients (2008)

p.H62L is definitely a nonclassical (congenital adrenal hyperplasia) mutation. (J Clin Endocrinol Metab 93: 2416 –2420, 2008)
The p.H62L reduced the enzyme activity to 44 and 21% for 17OHP and progesterone, respectively (Fig. 1A). Kinetic parameters were investigated for this mutation. Data indicate a reduction in the maximum velocity when compared with wild type (t test, P 0.05), whereas the Michaelis-Menten constant values were in the same range of magnitude for both substrates (Fig. 1B). For comparison purposes, p.P453S activity was evaluated under the same experimental conditions as for the p.H62L. Individually, both mutations have similar effects on enzyme activity (Fig. 1A). However, when the p.H62L mutation was expressed in combination with the p.P453S mutation, the activity of the enzyme was reduced to 4.1 and 2.3% toward 17OHP and progesterone, respectively, indicating a synergistic effect.

This mutation was originally listed as Pathogenic until 2015 when it was downgraded to Benign. I spoke to the PhD Director of Genomic Analysis, who was responsible for the downgrade who clarified:

Our classification of this variant is based on a comparison with the prevalence of congenital adrenal hyperplasia.

I have several other more common mutations (present in 40% of the population), but interestingly have another significant mutation associated with CAH and 21-hydroxylase.

rs6472(C/G) g1645G>C - Frequency 13% : ClinVar : Congenital adrenal hyperplasia 21-hydroxylase deficiency not specified

While those with classical CAH can present with EDS due to contiguous gene deletion, it's becoming increasingly likely that the entirety of the Hypermobile-Type may be a consequence of a yet undefined type of mild non-classical CAH due to abnormal and deficient production of 21-hydroxylase. 'NCAH1-X' is a fitting name for those with hypermobility, and NCAH1 for those without.

While NCAH usually presents with an androgen excess and responds to progesterone, NCAH1 has a variable production depending on stress response - and progesterone may make someone with a yet undefined NCAH1 mutation significantly worse.

Here are some recent studies discussing CAH-X

This post on Hypermobility Spectrum Disorder (HSD) goes into a bit more detail.

High-Throughput Screening for CYP21A1P-TNXA/TNXB Chimeric Genes Responsible for Ehlers-Danlos Syndrome in Patients with Congenital Adrenal Hyperplasia (2019)

Many patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency have CAH-X syndrome, a connective tissue dysplasia consistent with hypermobility-type Ehlers-Danlos syndrome due to a contiguous gene deletion involving the adjacent CYP21A2 and TNXB genes. CAH-X syndrome is caused by carrying CYP21A1P-TNXA/TNXB chimeric genes (CAH-X CH-1 and CH-2) on one or more alleles. Genetic analysis is cumbersome due to pseudogene interference. We developed a PCR-based CAH-X high-throughput screening method to assess the copy numbers of TNXB exons 35 and 40

Tenascin-X, Congenital Adrenal Hyperplasia, and the CAH-X Syndrome (2018)

Mutations of the CYP21A2 gene encoding adrenal 21-hydroxylase cause congenital adrenal hyperplasia (CAH). The CYP21A2 gene is partially overlapped by the TNXB gene, which encodes an extracellular matrix protein called Tenascin-X (TNX). Mutations affecting both alleles of TNXB cause a severe, autosomal recessive form of Ehlers-Danlos syndrome (EDS). Rarely, patients with severe, salt-wasting CAH have deletions of CYP21A2 that extend into TNXB, resulting in a “contiguous gene syndrome” consisting of CAH and EDS. Heterozygosity for TNXB mutations causing haploinsufficiency of TNX may be associated with the mild “hypermobility form” of EDS, which principally affects small and large joints.Studies of patients with salt-wasting CAH found that up to 10% had clinical features of EDS, associated joint hypermobility, haploinsufficiency of TNX and heterozygosity for TNXB mutations, now called “CAH-X.” These patients have joint hypermobility and a spectrum of other comorbidities associated with their connective tissue disorder, including chronic arthralgia, joint subluxations, hernias, and cardiac defects. Other disorders are beginning to be associated with TNX deficiency, including familial vesicoureteral reflux and neurologic disorders. Further work is needed to delineate the full spectrum of TNX-deficient disorders, with and without associated CAH.
Some people with a condition called benign joint hypermobility syndrome (BJHS) also make a reduced amount of tenascin-X protein, although no TNXB gene mutations have been identified in these individuals. This condition causes hypermobility and chronic joint pain. The signs and symptoms of benign joint hypermobility syndrome overlap significantly with those of the hypermobile type of Ehlers-Danlos syndrome. Studies suggest that they may be forms of the same condition.

Ehlers–Danlos Syndrome Caused by Biallelic TNXB Variants in Patients with Congenital Adrenal Hyperplasia (2016)

Novel ways in which TNX is disrupted, including the novel TNXA/TNXB chimera described here, represent potential genetic causes of hypermobile EDS of unknown etiology and requires further study

Diagnosis and management of the patient with non-classic CAH due to 21-hydroxylase deficiency (2018)

NCAH is a relatively common disorder regardless of ethnicity, but most cases are never diagnosed, especially in males. A baseline measurement of 17OHP may be used for screening, but the ACTH stimulation test with a measurement of 17OHP is the gold standard. We advocate a CYP21A2 mutation analysis to verify the diagnosis, for genetic counselling and for better prognostic and treatment guidance. Most patients are diagnosed in adolescence and adult life with hirsutism, acne, a PCOSlike picture and fertility issues. Many men with NCAH may never seek medical attention and therefore escape diagnosis. Although treatment is somewhat controversial, an early diagnosis and start of treatment may have positive implications on growth and be relevant for preventing and ameliorating the symptoms and consequences of androgen excess that develop over time. Glucocorticoids will improve symptoms of androgen excess and fertility, but they may result in long-term complications, such as obesity, insulin resistance, hypertension, osteoporosis and fractures. It is important to know that treatment will lead to a secondary cortisol insufficiency. Regular clinical monitoring to avoid risk factors and improve the clinical outcome is recommended. Studies focusing on the specific difficulties patients with NCAH face, both those with a late clinical diagnosis and those with a neonatal diagnosis obtained by screening, are warranted

The Complexities in Genotyping of Congenital Adrenal Hyperplasia: 21-Hydroxylase Deficiency (2019)

Functional and Structural Consequences of Nine CYP21A2 Mutations Ranging from Very Mild to Severe Effects (2016)

Results for 'RCCX' in our DNA database. Database