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Autoimmune Disease, Multisystem, with Facial Dysmorphism (ADMFD) is an autosomal recessive disorder caused by biallelic pathogenic variants in ITCH and characterized by failure to thrive, dysmorphic facial features, developmental delay, and systemic autoimmunity (Syndromic Multisystem Autoimmune Disease due to ITCH Deficiency). Core features include abnormal facial shape (HP:0001999), global developmental delay (HP:0001263), failure to thrive (HP:0001508), thyroiditis (HP:0100646), and enteropathy with abnormal intestine morphology (HP:0002242).
Thirteen unrelated probands (10 consanguineous Old Order Amish, one White British, one Black German, one Caucasian female) harbor homozygous or compound heterozygous loss-of-function ITCH variants, including a recurrent frameshift c.603del (p.Ile132AsnfsTer9), segregating with disease in multiple pedigrees ([PMID:36338154]).
Patient-derived fibroblasts exhibit complete absence of ITCH protein, a mitochondrial DNA copy number of 57% relative to controls, markedly decreased mitochondrial fatty acid β-oxidation and oxidative phosphorylation activities, and reduced ATP production, confirming mitochondrial bioenergetic dysfunction as a disease mechanism ([PMID:36338154]).
ITCH encodes a HECT-domain E3 ubiquitin ligase involved in apoptosis and immune regulation. Loss of ITCH disrupts normal protein turnover and energy homeostasis, driving the multi-system autoimmune phenotype and offering potential targets for metabolic modulation.
No conflicting reports have disputed this association. Further studies in additional cohorts and in vivo models may expand the phenotypic spectrum and refine therapeutic approaches.
Key Take-home: Biallelic ITCH deficiency is definitively associated with a syndromic multisystem autoimmune disorder featuring mitochondrial dysfunction, informing molecular diagnosis and potential metabolic intervention strategies.
Gene–Disease AssociationStrong13 probands across at least three independent ethnic groups, segregation in consanguineous Old Order Amish families, protein absence and functional concordance ([PMID:36338154]) Genetic EvidenceStrongBiallelic loss-of-function ITCH variants in 13 probands from multiple pedigrees, including consanguineous families ([PMID:36338154]) Functional EvidenceModeratePatient fibroblasts lack ITCH protein, show mtDNA depletion, reduced β-oxidation, impaired OXPHOS and ATP production, consistent with disease mechanism ([PMID:36338154]) |