Categories: Respiratory system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 605883 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive lethal

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2020

Species-specific name: Fatal neonatal interstitial lung disease

History: This canine disorder was first described by Dillard et al. (2020), who also reported discovering a likely causal variant.

Inheritance: Dillard et al. (2020) genotyped "20 additional adult, non-affected AT dogs" for the LAMP3 variant. "As they were screened, one of these dogs, a dam that had had a litter that included affected puppies, turned out to be homozygous for the LAMP3 variant . . . . At the time of sampling, the dam was 6 years of age and, according to its owner, had been clinically healthy all its life without any signs of respiratory disease. To study the possible differences of the variants in the associated locus between the dam and the affected puppy, the whole genome of the dam was also sequenced and compared with the affected puppy. This analysis did not reveal any dam-specific heterozygous variants, which would have indicated that our LAMP3 variant is not causal but instead in LD with the true disease-causing variant. In contrast, this result suggests that the dam may have an unknown protective variant".

Mapping: Dillard et al. (2020): "A GWAS with 5 affected and 24 unaffected AT dogs revealed 198 SNPs with genome-wide significance on chromosome 34 between 12,013,938–22,402,691 bp . . . . Fifteen most significant SNPs (praw = 7.161 × 10−10, pBonferroni = 6.689 × 10−5) were located at 15,092,907–17,132,621. Assessment of the genotypes revealed a 3.9 Mb homozygous region at 13,290,333–17,170,957 in the affected puppies".

Molecular basis: Dillard et al. (2020): "A combined approach of genome-wide association study and whole exome sequencing identified a recessive variant, c.1159G>A, p.(E387K), in LAMP3, a limiting membrane protein of the cytoplasmic surfactant organelles in AECII [alveolar epithelial type II] cells".

Clinical features: Dillard et al. (2020): "All 25 affected puppies were born at term with normal delivery. One was stillborn. Six (24%) were lethargic at birth, refused to suckle and developed dyspnea or tachypnea and died or were humanely euthanized at 4–18 hours later. The rest of the puppies (72%) were initially normal until the difficulties in breathing started. Most of these puppies died during one to four days (64%), except one puppy that survived for 7 days and one up to 4 weeks. Full necropsy was performed for the 25 puppies and the main lesion was in the lungs. The lungs of all the puppies, except the 4-week-old, were edematous, congested and appeared poorly aerated . . . . At four weeks the lungs had a rubbery texture and marked emphysema . . . . No significant macroscopic changes were detected in other organs."

Prevalence: Dillard et al. (2020) genotyped the LAMP3 likely causal variant "in 371 affected and control AT dogs and found that . . . [the variant] fully segregated with the disease under recessive model (25/371 homozygous mutant, 77/371 heterozygous carrier, 269/371 homozygous wild type) . . . . In this cohort, the carrier frequency was 20.6%. . . . Finally, to investigate the breed specificity of the LAMP3 variant, we screened additional 6940 dogs from 297 breeds, including eight Airedale Terriers . . . . Only one heterozygous dog, an Airedale Terrier, was identified, which indicates that the LAMP3 variant is specific to the breed".

Breed: Airedale Terrier (Dog) (VBO_0200008).
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: