Categories: Haematopoietic system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 134820 (gene) , 202400 (trait)

Links to relevant human diseases in MONDO:

• MONDO:0008737: congenital afibrinogenemia

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2021

Species-specific description: Mischke et al. (2021): “we present a family of miniature wire-haired Dachshunds segregating for congenital afibrinogenemia. We employed homozygosity mapping, a genome-wide association study (GWAS), and sequencing of fibrinogen genes in order to identify a mutation responsible for afibrinogenemia.”

Mapping: Mischke et al. (2021): “ Homozygosity mapping and a genome-wide association study identified a candidate genomic region at 50,188,932–64,187,680 bp on CFA15 harboring FGB (fibrinogen beta chain), FGA (fibrinogen alpha chain), and FGG (fibrinogen gamma-B chain).”

Molecular basis: Mischke et al. (2021): “Sanger sequencing of all three fibrinogen genes in two cases and validation of the FGA-associated mutation (FGA:g.6296delT, NC_006597.3:g.52240694delA, rs1152388481) in pedigree members showed a perfect co-segregation with afibrinogenemia-affected phenotypes, obligate carriers, and healthy animals. In addition, the rs1152388481 variant was validated in 393 Dachshunds and samples from 33 other dog breeds. The rs1152388481 variant is predicted to modify the protein sequence of both FGA transcripts (FGA201:p.Ile486Met and FGA-202:p.Ile555Met) leading to proteins truncated by 306 amino acids.”

Clinical features: Mischke et al. (2021): “Three seven-week-old miniature wire-haired Dachshunds were presented … with excessive bleedings after fitting with a chip two days before. Two puppies were female and one male. One female died a few days later due to severe bleedings. The second female puppy survived up to an age of one year. Owners reported recurrent episodes with severe bleedings in the skin and gums. The third affected male puppy is under intensive veterinary care and still alive at the age of seven years despite intermittent severe bleeding episodes. … Case 4 … died from a hemoabdomen after a traumatic splenic rupture."

Pathology: Mischke et al. (2021): "In the affected dogs, PT [Prothrombin time](standard test), aPTT [activated partial thromboplastin time], and TT [thrombin time assay] exceeded the upper limits of detection (>200 s). PT measured with the optimized assay revealed increased or normal activities of factors II, V, VII, and X, respectively (case 1: 149%; case 2: 104%; case 3: 126%; 100% = average of normal adult dogs) and a moderate reduction in case 4 (44%, reference range in adult dogs: 75–130%). Fibrinogen concentration according to the coagulometric Clauss method was below the lowest detection limit in all four cases (<0.2 g/L; reference 1.0–3.0 g/L). Platelet count was normal in all four affected animals suffering from bleeding complications.”

Breed: Dachshund, Miniature Wire-Haired (Dog) (VBO_0200411).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: