Migraine is a disabling neurological disorder burdening patients globally. Through the increasing development of preclinical and clinical experimental migraine models, advancing appreciation of the extended clinical phenotype, and functional neuroimaging studies, we can further our understanding of the neurobiological basis of this highly disabling condition. Despite increasing understanding of the molecular and chemical architecture of migraine mechanisms, many areas require further investigation. Research over the last three decades has suggested that migraine has a strong genetic basis, based on the positive family history in most patients, and this has steered exploration into possibly implicated genes. In recent times, human genome-wide association studies and rodent genetic migraine models have facilitated our understanding, but most migraine seems polygenic, with the monogenic migraine mutations being considerably rarer, so further large-scale studies are required to elucidate fully the genetic underpinnings of migraine and the translation of these to clinical practice. The monogenic migraine mutations cause severe aura phenotypes, amongst other symptoms, and offer valuable insights into the biology of aura and the relationship between migraine and other conditions, such as vascular disease and sleep disorders. This review will provide an outlook of what is known about some monogenic migraine mutations, including familial hemiplegic migraine, familial advanced sleep-phase syndrome, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. 

Genetic Mechanisms of Migraine: Insights from Monogenic Migraine Mutations

Background Autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebrovascular disease closely related to the NOTCH3 gene. More than 200 mutations in this gene have been reported to be associated with this disease. Methods The NOTCH3 gene from CADASIL patient was screened for mutations by whole-exome sequencing (WES). PCR amplification and direct Sanger sequencing were used to verify the suspicious gene mutation sites detected by WES. Results We performed second-generation sequencing on a sample of the patient's genome and found a heterozygous deletion-insertion mutation c.512_605delinsA in exon 4 of NOTCH3, which resulted in amino acid changes p.G171_A202delinsE. This variation was confirmed by the direct Sanger sequencing. It may be rated as a CADASIL clinical variation. Conclusion Discovery of this mutation site provides an important theoretical basis for specific gene-based diagnosis and treatment of CADASIL.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcla.24027

A case of CADASIL caused by NOTCH3 c.512_605delinsA heterozygous mutation.

Rationale: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease caused by the neurogenic locus notch homolog protein 3 ( NOTCH3 ) gene mutation. In recent years, most of the newly reported mutations of CADASIL patients mainly occur in exon 3 to 24, while the cases related to exon 2 mutation are rare, and clinical research data are relatively insufficient. In this study, we have reported a case of a rare heterozygous mutation c.128G&gt;A (p.Cys43Tyr) in exon 2 of NOTCH3 in a 41-year-old Chinese man in the light of relevant literatures. Patient concerns: A 41-year-old man who suffered slurred speech for 5 days and right lower limb weakness for 4 days was admitted to our hospital. Diagnoses: Magnetic resonance imaging of the head revealed diffuse white matter lesions involving the outer capsular area and bilateral temporal poles. The rare heterozygous mutation c.128G&gt;A (p.Cys43Tyr) in exon 2 of NOTCH3 was identified through molecular genetic testing. The proband was diagnosed as having CADASIL. Meanwhile, the same mutation was detected in 2 other family members III5 and IV9. Interventions: Atorvastatin calcium tablet (20 mg qd) and aspirin enteric-coated tablet (100 mg qd). Outcomes: The patient was hospitalized for 3 weeks and discharged after his symptoms improved. Lessons: The heterozygous Cys43Tyr mutation in exon 2 of NOTCH3 is rare. Thus, our case report complements the rare mutation of exon 2 and offers additional clinical data for CADASIL patients. 

A Chinese CADASIL family with a rare heterozygous mutation in exon 2 of NOTCH3: A case report

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A case of CADASIL caused by NOTCH3 c.512_605delinsA heterozygous mutation.