Submission Details

FAM111B was first reported in relation to autosomal dominant hereditary sclerosing poikiloderma in 2013 (Mercier S et al., PMID: 24268661). Key features of the syndrome include fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP). The poikiloderma affects all patients and seems to evolve in two phases: an early phase characterized by a facial photo-induced erythema before 6 months of age, and a chronic phase consisting of progressive atrophic skin changes that persist throughout life. Dermatologic features can include erythrosis and hyperlinearity of the hands and feet, progressive scarring alopecia, sparse or absent eyebrows and/or eyelashes, hypohidrosis with heat intolerance, and scleroderma-like skin changes. Other features of this syndrome include muscle contractures, especially of the triceps, diffuse progressive fatty myopathy, pulmonary fibrosis in adulthood, and exocrine pancreatic insufficiency. FAM111B encodes a protein with a putative trypsin-like cysteine/serine peptidase domain in the C-terminus (O'Leary NA et al., 2016, PMID: 26553804) and most mutations are clustered in this domain.

Twelve variants (11 missense, 1 in-frame deletion) reported in 21 probands in 13 publications were included in this curation (Mercier et al., 2013, PMID:24268661; Mercier et al., 2015, PMID: 26471370; Seo et al., 2016, PMID: 26495788; Dokic et al., 2020, PMID: 33294546; Roversi et al., 2021, PMID: 34358284; Goussot et al., 2017, PMID: 28349113; Wu et al., 2022, PMID: 36092869; Takeichi et al., 2017, PMID: 27406236; Chen et al., 2019, PMID: 30938824; Zhang et al., 2019, PMID: 31392773; Ferré et al., 2023, PMID: 36875114; Hoeger et al., 2023, PMID: 36102338; Sato et al., 2022, PMID: 35601499). The mechanism of disease for POIKTMP is not known; however, the spectrum of pathogenic variants suggest a gain-of-function or dominant-negative mechanism leading to altered enzymatic activity (Mercier et al 2015, PMID: 26471370).

This gene-disease relationship is supported by experimental evidence. FAM111B knockout cells show that the protein plays a role in proliferation and cell cycle progression of KRAS-driven lung cell lines under serum starvation conditions (PMID 32418298). Biochemical studies suggest that FAM111B forms a complex with its homolog FAM111A. Its proteolytic activity is apparently dispensable for normal cell growth. However, disease-associated FAM111B variants have amplified proteolytic activity and phenocopy FAM111A mutant cellular phenotypes including suppression of DNA replication and transcription as well as triggering cell death via caspase-dependent apoptosis (PMID 32776417). Other experimental evidence includes altered expression of FAM111B in skin fibroblasts from a South African patient with the Y621D variant (Rhoda C et al., 2023, PMID: 36610347).

In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Interstitial Lung Disease Gene Curation Expert Panel on the meeting date 12/19/2023 (SOP Version 9).

Twelve variants (11 missense, 1 in-frame deletion) that have been reported in approximately 21 probands in 13 publications (Mercier et al., 2013, PMID:24268661; Mercier et al., 2015, PMID: 26471370; Seo et al., 2016, PMID: 26495788; Dokic et al., 2020, PMID: 33294546; Roversi et al., 2021, PMID: 34358284; Goussot et al., 2017, PMID: 28349113; Wu et al., 2022, PMID: 36092869; Takeichi et al., 2017, PMID: 27406236; Chen et al., 2019, PMID: 30938824; Zhang et al., 2019, PMID: 31392773; Ferré et al., 2023, PMID: 36875114; Hoeger et al., 2023, PMID: 36102338; Sato et al., 2022, PMID: 35601499), are included in this curation. The mechanism of disease for POIKTMP is not known; however, the spectrum of pathogenic variants and functional studies suggest a dominant-negative mechanism (Mercier et al 2015, PMID: 26471370).

This gene-disease relationship is also supported by experimental evidence including biochemical function of decreased FAM111B gene expression which can result in inadequate DNA repair, genome instability which results in apoptosis which may, in turn, trigger chronic inflammation (Arowolo A et al., 2022, PMID: 35860584). Other biochemical mechanisms include expression of FAM111B in skin fibroblast from a South African patient with Y621D variant. (Rhoda C et al., 2023, PMID: 36610347). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Interstitial Lung Disease Gene Curation Expert Panel on the meeting date 8/15/2023 (SOP Version 9).