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NOTCH3 Gene Mutation

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a microangiopathy that causes decreased blood supply to the brain. Clinical presentation varies among and within familes. CADASIL is characterized by five main symptoms:

  • History of migraine with aura
  • Mid-adult onset of transient ischemic attacks and ischemic stroke,
  • Mood disturbance with severe depressive episodes
  • Apathy
  • Cognitive disturbance progressing to dementia

Neuroimaging reveals diffuse white matter lesions and subcortical infarcts on neuroimaging. Skin biopsy and electron microscopy examination of small arterioles demonstrates characteristic granular osmophilic deposits within the vascular media close to smooth muscle cells that immunostain positive for NOTCH3 protein.

The Notch signaling pathway is an intercellular signaling mechanism that plays a central role during vascular development and physiology. Notch 3 is primarily expressed in vascular smooth muscle cells. Most NOTCH3 mutations are missense mutations, leading to the loss or gain of a cysteine residue in NOTCH3 protein and a change in its tertiary structure. It is not known how the abnormal protein impairs vascular function.

CADASIL is inherited in an autosomal dominant manner. Most affected individuals have an affected parent; de novo mutations are rare. Occasionally, family history may appear to be negative because of failure to recognize the disorder in family members, early death of a parent before onset of symptoms, or late onset of the disease in the affected parent. Each child of an affected person is at a 50% risk of inheriting the mutation and developing signs of the disease. Offspring of a person who is homozygous or compound heterozygous have 100% risk of inheriting a mutation.

NOTCH3 is the only gene in which mutations have been associated with CADASIL. More than 90% of individuals have mutations in NOTCH3. Penetrance of the disease is probably 100%, but expression varies in age of onset, severity, and disease progression.  

Most mutations in NOTCH3 are located in exon 4, followed by exons 3, 5, 6, and 11. Almost 90% of mutations occur in exons 2 through 6. Some laboratories perform simultaneous sequencing of these exons while others start with exons 2-6 and perform serial sequencing as necessary.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of proband’s mutation. The risk to the sibs of the proband depends on the genetic status of the proband's parents. If a parent of the proband is affected, the risk to sibs is 50%. If the proband is homozygous for a NOTCH3 mutation and both parents are heterozygous, the risk to the sibs of the proband of having at least one NOTCH3 mutation is 75%. The family should be referred to a genetics counselor. 

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