The study, “Double somatic mosaicism in a child with Dravet syndrome,” was published in Neurology Genetics.
Dravet syndrome, a severe type of epilepsy usually evident during the first year of life, is in about 80% of cases tied to known mutations in the SCN1A gene, which encodes for a sub-unit of a sodium channel called NaV1.1 that is involved in the transmission of electrical signals in the brain.
In about 20% of Dravet patients, however, the disorder’s cause is unclear. In these cases, it has been proposed that genetic alterations taking place in very early fetal development, and not inherited from the parents, may be the underlying reason.
Investigators at the University of Washington examined whether somatic mosaicism — a phenomenon in which an individual has cells that are genetically different due to a mutation taking place during very early fetal development (shortly after the embryo formed) — could be the reason why some people develop idiopathic (unknown cause) Dravet syndrome.
They used a highly sensitive technique known as deep sequencing to analyze SCN1A and seven other genes previously linked with the disease (SCN2A, SCN8A, HCN1, GABRA1, GABRG2, STXBP1, and PCDH19) using DNA they isolated from blood or saliva of 20 patients with this type of Dravet syndrome.
Remarkably, a 12-year-old girl who had somatic mosaicism and carried two different genetic mutations affecting the same nucleotide (the building blocks of DNA) position in the sequence of SCN1A: g.166848363A > G (adenine replaced by guanine) and g.166848363A > C (adenine replaced by cytosine).
Both variants were present at low frequencies in the child’s blood — 8.3% for g.166848363A > G and 6.9% for g.166848363A > C — and is normally undetectable using more common genetic sequencing methods.
Both variants led to the replacement of the amino acid (the building blocks of proteins) phenylalanine in the protein sequence, either by leucine in the first variant (Phe1808Leu) or by valine (Phe1808Val) in the second. Further analyses showed both variants were located on the SCN1A copy the girl inherited from her father.
As a 6-month-old, the girl started experiencing febrile generalized tonic-clonic seizures that continued until she reached age 1. When she was 2 years old, she started having seizures grouped in clusters, and experienced her first status epilepticus by the age of 3.
She started showing signs of language deficits at age 2 and was diagnosed with attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Despite treatment with several medications (valproate, carbamazepine, lamotrigine, topiramate, clobazam, and cannabidiol), her seizures were never kept under control.
“We detected double mosaicism in SCN1A in a patient with Dravet syndrome. Comprehensive studies of disease-relevant tissue will be required to gain a more accurate picture of somatic mosaicism levels and how this affects disease severity,” the scientists concluded.