Interpretation of NOTCH3 mutations in the diagnosis of CADASIL

Abstract

CADASIL is an autosomal dominant inherited disease, characterized by mid-adult onset of cerebrovascular disease and dementia. CADASIL is caused by mutations in the NOTCH3 gene, which encodes the NOTCH3 protein. Pathogenic mutations in CADASIL are highly distinctive in the sense that they lead to the loss or gain of a cysteine residue in 1 of the 34 EGFr domains of the NOTCH3 protein. The majority are missense mutations, but small deletions, insertions and splice-site mutations have been reported, which typically also lead to a numerical cysteine alteration. Whether numerical cysteine-altering mutations are a rule in CADASIL remains subject of debate, as there are reports suggesting pathogenicity of other types of mutations. However, for most of these the association with CADASIL was later revoked or is questionable. Here, we discuss and provide recommendations for the interpretation of NOTCH3 mutations in the diagnosis of CADASIL.

Keywords::

• CADASIL
• dementia
• diagnosis
• NOTCH3
• stroke

Financial & competing interests disclosure

JW Rutten is funded by ZonMw, the Netherlands Organization for HEALTH Research and Development; SAJ Lesnik Oberstein is partially funded by ZonMw. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by gain-of-function mutations in NOTCH3, leading to toxic NOTCH3 accumulation in the vessel wall.

• Only NOTCH3 mutations that alter the number of cysteines in 1 of the 34 EGFr domains of the NOTCH3 protein have been proven to cause CADASIL:

  • – The great majority are missense mutations.

  • – Mutations are found only in EGFr-encoding exons (2–24).

  • – Most mutations are located in exon 4.

• Some CADASIL patients with homozygous and compound heterozygous mutations have been described. The symptoms of these patients seem to be within the normal CADASIL spectrum.

• Small NOTCH3 in-frame deletions, insertions or splice-site mutations can also cause CADASIL. These typically also alter the number of cysteines in 1 of the 34 EGFr of NOTCH3.

• Mutations in NOTCH3 leading to loss of NOTCH3 function do not cause CADASIL. These rare mutations include mutations leading to a frameshift and stop mutations.

• Missense mutations in NOTCH3 not altering a cysteine residue are unlikely to be pathogenic, and should be considered coincidental findings, until proven otherwise. If such a mutation is detected, the following should be considered:

  • – A coinciding cysteine-altering mutation may have been missed due to technical reasons or incomplete sequencing analysis.

  • – The clinical diagnosis of CADASIL may be incorrect and should be confirmed by electron microscopy and NOTCH3 immunohistochemistry on a skin biopsy.

Notes