Causes

SIOD is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

Two mutations in the swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAl1) gene are found in 50 to 60% of individuals clinically diagnosed with SIOD. The individuals without detectable mutations in SMARCAL1 have a lower frequency of hyperpigmented macules and lymphopenia and higher frequency of cognitive impairment. This suggests that they have might have a subtly different disorder or SIOD secondary to another genetic cause.

The mutations identified in SMARCAL1 suggest that SIOD arises from loss of function in the encoded protein. These mutations include gene deletions as well as nonsense, frame shift, splicing and missense mutations. Mutations in SMARCAL1have not been found to cause any other disease.

With the exception of the sibling of an affected patient, all identified patients with two mutations in SMARCAL1 have had SIOD and none of the tested unaffected siblings have had two mutations. The asymptomatic boy with two mutations was 2 years when first described and may develop symptoms later.

Despite extensive analysis, there are no predictable relationships between particular SMARCAL1 mutations and the severity of the symptoms or the outcome. This has led to the idea that SIOD is the result of the interaction between the SMARCAL1 mutations and environmental, genetic, and epigenetic factors.

The SMARCAL1 gene encodes the SMARCAL1 enzyme which has a role in DNA repair and the DNA stress response, participates in activating stalled DNA replication forks and reannealing single stranded DNA to double stranded DNA. SMARCAL1 deficiency in tissue culture cells also impairs normal replication of telomere DNA at the ends of the chromosomes. Recent studies of some SIOD patients with SMARCAL1 deficiency caused by two SMARCAL1 mutations has found significantly shortened telomeres in white blood cells, including T cells. The deficiency of SMARCAL1 causes non-random, global changes in gene expression and changes in gene expression cause the arteriosclerosis, renal disease and immunodeficiency. The arteriosclerosis appears to be a consequence of reduced expression of elastin. The renal disease appears to arise from overexpression and activity of the WNT and NOTCH pathways. The T-cell deficiency arises from lack of expression of IL7 receptor alpha chain expression and is associated with hypermethylation of the IL7R promotor as well as the shortened telomere length. These changes in gene expression might well develop from the changes in epigenetic marks associated with replication fork stalling and collapse.

- National Organization for Rare Disorders

https://rarediseases.org/rare-diseases/schimke-immuno-osseous-dysplasia/