Objective: *Authors EMF and DAO contributed equally. To describe the phenotype of the second reported pedigree with the heterozygous splicing mutation c.823-10G>T at the intron 9/exon 10 of the MAPT gene.

Background: 20-30% of frontotemporal lobar degeneration is hereditary and 15-20% of these patients carry MAPT mutations. Mutations can be coding missense or deletions or rarely intronic close to the splice-donor site 3′ of the alternatively spliced exon 10. C.823-10G>T is a previously reported MAPT variant strengthening the polypyrimidine tract and affecting the splicing of exon 10.

Methods: A 50-year-old Irish man (III:1) developed difficulty in concentration and was not able work. He became distant, depressed and behaved inappropriately. By 54 he was stiff and began to fall. He was diagnosed with FTDP-17 at 61. He was moved to a nursing home, became wheelchair bound and anarthric. The proband’s brother (III:2) became “odd” in his 40s (eg, he took a half-eaten apple from a bin), aggressive, forgetful. He was diagnosed with FTD and died in a nursing home at 59. The second brother (III:4) developed dementia in his 40s. He became “odd”, withdrawn and died at age 53. The proband’s sister (III: 6) at age 50 was forgetful, withdrawn, often vulgar and died at 61. None of the siblings had genetic testing. The proband’s mother developed dementia in late 70s and died in a nursing home at 88. The proband’s maternal aunt behaved oddly, was forgetful and died in a nursing home. The proband’s father at 43 was short tempered, forgetful, kept sweets in his pocket, was “childish”, made mistakes in his job, and would attend multiple church services on a Sunday. He died at age 53.

Results: Proband: MRI brain showed a very severe temporal and frontal lobes atrophy. Fluorescing sequencing of the proband showed a heterozygous splicing mutation c.823-10G>T at the intron9/exon 10 of the MAPT gene (g. 123701 g>T).

Conclusions: To date there is only 1 family described with c.823-10G>T mutation co-segregating with the disease (mean age of onset: 42.7 (38-49), mean age at death: 50 y (50-50), mean disease duration: 9.0 y (9-9)). We expand the phenotype and describe the only other known family carrying this mutation (proband’s later onset age: 50, disease duration: 15 years, still alive at 65). We strengthen the argument that this variant is pathogenic (second family, different country).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-heterozygous-splicing-mutation-c-823-10gt-at-the-intron9exon-10-of-the-mapt-gene-in-an-irish-family-with-ftdp-17/