ETFDH

Inheritance Pattern: AR

Disease ID:MONDO:0009282

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009282

Submitter: ClinGen

*ETFDH* (MIM 231675) was first reported in relation to autosomal recessive multiple acyl-CoA dehydrogenase deficiency in 2003 (PMID: 12815589). This disorder affects fatty acid oxidation and electron transfer, presenting with metabolic acidosis, hypoglycemia, hypotonia, hepatomegaly, and variable onset from neonatal to adulthood. Twenty-one variants (including missense, nonsense, frameshift, and splice-site changes) have been reported in 19 probands in 11 publications (PMIDs: 12815589, 17584774, 19249206, 19265687, 20020044, 22013910, 22580358, 22611163, 24123825, 29249369, 2989828). These variants include missense changes in highly conserved residues within the FAD-binding domain (e.g., p.Ala84Thr, p.Arg175Leu), frameshift variants (e.g., c.51dupT), splice-site alterations (e.g., c.405+3A>T), and nonsense mutations. Functional studies demonstrate that several missense variants markedly reduce ETFDH activity and impair riboflavin responsiveness, while null variants result in absent protein expression in patient fibroblasts (PMIDs: 2989828, 22611163). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Experimental evidence further supports this gene-disease relationship. *ETFDH* encodes electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO), a key component of mitochondrial β-oxidation, and its deficiency disrupts energy metabolism, leading to characteristic biochemical abnormalities (PMID: 3620453). Patient cells show absent ETF-QO protein and activity (PMID: 2989828), and non-patient cell assays confirm reduced activity of mutant proteins under riboflavin-limited conditions (PMID: 22611163). Zebrafish and fruit fly models with ETFDH disruption exhibit metabolic profiles similar to those observed in affected individuals, including accumulation of acylcarnitines and mitochondrial dysfunction (PMIDs: 20020044, 22580358). In summary, there is definitive evidence to support the relationship between *ETFDH* and autosomal recessive MADD. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen FAO GCEP on the meeting date 2018 May 22 (SOP Version 6). ETFDH: Data provided by the ClinGen Prenatal GCEP from July 9, 2025 secondary analysis Multiple acyl-CoA dehydrogenation deficiency (MADD) is an autosomal recessive disorder of fatty acid oxidation due to deficiency of the mitochondrial electron transfer chain. MADD can be caused by deficiencies in any of three proteins electron transfer flavoprotein (ETF) system, including ETFA, ETFB, and ETFDH. Pathogenic variants in the *ETFDH* gene are the most common cause of MADD and represent approximately 93% of cases. Although genetically heterogeneous, there does not appear to be a difference in clinical phenotypes. The severity of disease is correlated with residual protein function and ranges from a severe neonatal form with or without congenital anomalies to a milder, later onset form. Neonatal forms present with hypotonia, severe metabolic acidosis, hyperammonemia, hypoglycemia, respiratory distress, hepatomegaly, and a sweaty feet odor. Prenatal features and congenital physical anomalies can include cystic/dysplastic kidneys with sequelae of oligohydramnios/anhydramnios, hypertrophic cardiomyopathy, dysmorphic facial features including midface hypoplasia, tented upper lip, low set ears, or high anterior hairline. Most severely affected newborns die in the first week of life. (PMID 12815589, 36406819, 32959991)

Inheritance Pattern: AR

Disease ID:MONDO:0009282

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009282

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0009282

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009282

Submitter: Ambry Genetics