NHLRC2 – FINCA syndrome

FINCA syndrome (fibrosis, neurodegeneration, and cerebral angiomatosis) is an autosomal recessive multisystem disorder caused by biallelic variants in NHLRC2. Affected individuals present in infancy with progressive interstitial lung disease, recurrent infections, hepatic steatosis, chronic hemolytic anemia and malabsorption, often accompanied by early-onset neurodevelopmental delay and cerebral angiomatosis.

Genetic evidence includes at least 27 probands from over 20 unrelated families with compound heterozygous or homozygous NHLRC2 variants, consistent with autosomal recessive inheritance ([PMID:29423877]; [PMID:34165204]; [PMID:35255187]; [PMID:37188825]). Variant spectrum comprises recurrent missense changes—most notably c.442G>T (p.Asp148Tyr)—and multiple predicted loss-of-function alleles including frameshift and stop-gains, supporting a loss-of-function mechanism.

Functional studies reveal that the Trx-like and NHL repeat β-propeller domains form a conserved cleft, with the recurrent p.Asp148Tyr substitution reducing protein stability by ~2 °C ([PMID:30138417]). Morpholino knockdown in zebrafish disrupts midbrain integrity, and Nhlrc2 null mice are embryonic lethal. A knock-in mouse model harboring p.Asp148Tyr shows altered RNA-binding proteins, disrupted Rho GTPase signaling, neurobehavioral and immune defects mirroring human disease ([PMID:33297935]).

Mechanistically, NHLRC2 loss leads to reduced protein levels, impaired ligand-binding cleft stability, and disrupted vesicular transport and RNA metabolism, converging on fibrosis, neurodegeneration, and vascular anomalies.

No conflicting reports have been identified. The breadth of case series, segregation in multiple families, and concordant cellular and animal models provide robust support for a Strong gene–disease association.

Key Take-home: Biallelic NHLRC2 variants cause FINCA syndrome; genetic testing facilitates diagnosis, and emerging mechanistic insights may guide future therapeutic strategies.

References

• Acta neuropathologica • 2018 • NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease. PMID:29423877
• Clinical genetics • 2021 • Expanding the phenotypic spectrum of FINCA (fibrosis, neurodegeneration, and cerebral angiomatosis) syndrome beyond infancy. PMID:34165204
• Molecular genetics & genomic medicine • 2022 • FINCA syndrome-Defining neurobehavioral phenotype in survivors into late childhood. PMID:35255187
• European journal of human genetics : EJHG • 2023 • Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals. PMID:37188825
• PloS one • 2018 • Structural analysis of human NHLRC2, mutations of which are associated with FINCA disease. PMID:30138417
• Molecular medicine (Cambridge, Mass.) • 2020 • Variant in NHLRC2 leads to increased hnRNP C2 in developing neurons and the hippocampus of a mouse model of FINCA disease. PMID:33297935

Evidence Based Scoring (AI generated)