Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Biallelic variants in SPATA5 (HGNC:18119), encoding an AAA family ATPase, cause an autosomal recessive neurodevelopmental disorder characterised by microcephaly, intellectual disability, sensorineural hearing loss, epilepsy and abnormal muscle tone, formally designated microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (MONDO:0014698). SPATA5 is broadly expressed in neural and muscular tissues and contains a mitochondrial targeting sequence essential for its ATPase function. The association has been delineated through multiple case reports, cohort analyses and functional studies demonstrating concordant human and cellular phenotypes. Below, we summarise the genetic and experimental data supporting this gene–disease relationship.
Case series and cohort analyses have reported multiple families with biallelic SPATA5 variants. A consanguineous pedigree exhibited seven affected individuals with a homozygous in-frame deletion c.1822_1824del (p.Asp608del) segregating with disease (PMID:27683084). The same study described an unrelated individual carrying compound heterozygous c.2081G>A (p.Gly694Glu) and c.983CAA[2] (p.Thr330del) (PMID:27683084). An independent report detailed five patients from four pedigrees harbouring missense, in-frame deletion, nonsense and splice‐site variants (PMID:29343804). A family with two siblings carrying p.Thr330del and c.1714+1G>A illustrated variable expressivity with isolated hearing loss in one child (PMID:28293831). Subsequent single-case studies included an 8-year-old with compound heterozygous alleles assessed by proteomics (PMID:34360601) and another patient diagnosed via mitochondrial functional assays (PMID:36849973). The total of at least 17 probands across these cohorts, combined with full segregation in the consanguineous pedigree, underpins a Strong gene–disease association.
Inheritance is autosomal recessive with complete segregation in large and nuclear families. The variant spectrum comprises missense (e.g. c.2081G>A (p.Gly694Glu)), in-frame deletions (c.1822_1824del (p.Asp608del), c.983CAA[2] (p.Thr330del)), nonsense/frameshift (c.394C>T (p.Gln132Ter), c.250C>T (p.Arg84Ter)) and splice-site changes (c.1714+1G>A). All alleles are rare or absent from population databases. A recurrent p.Thr330del founder allele has been observed in diverse ancestries. Genotype–phenotype correlations suggest hypomorphic variants may yield milder or isolated hearing loss.
Functional studies demonstrate that SPATA5 localizes to mitochondria and regulates mitochondrial dynamics in neurons and muscle. Patient‐derived fibroblasts and rat cortical neurons deficient in SPATA5 exhibit imbalanced fusion–fission rates, reduced oxygen consumption and shortened axonal processes (PMID:29343804, PMID:36849973). Proteomic profiling of muscle biopsies revealed dysregulation of mitochondrial and related proteins alongside histological mitochondrial pathology (PMID:34360601). Molecular modelling predicts destabilization of ATPase domains by p.Asp608del and p.Gly694Glu variants (PMID:27683084). These concordant data support a loss-of-function mechanism.
No reports have refuted the SPATA5–MONDO:0014698 association or assigned alternative genetic causes in well‐characterized cohorts. The integration of autosomal recessive segregation, diverse variant classes and consistent functional deficits delineates a coherent pathomechanism. While additional rare alleles may emerge, current evidence meets ClinGen Strong criteria for gene–disease validity.
SPATA5 should be included in diagnostic panels for neurodevelopmental disorders with epilepsy and hearing loss, and in evaluations of isolated sensorineural hearing impairment. Early molecular diagnosis enables genetic counseling, prognosis and consideration of mitochondrial-targeted interventions. Further work may refine therapeutic strategies and elucidate genotype–phenotype nuances. Key take-home: Biallelic SPATA5 variants cause a distinctive autosomal recessive neurodevelopmental syndrome with mitochondrial dysfunction, underscoring its strong clinical utility for diagnostic testing.
Gene–Disease AssociationStrongAt least 17 probands across five unrelated lineages with full segregation in a consanguineous pedigree and concordant functional data Genetic EvidenceStrongMultiple families with biallelic missense, in-frame deletion, nonsense and splice variants segregating in autosomal recessive fashion Functional EvidenceModerateCellular and proteomic models demonstrate impaired mitochondrial dynamics, energy deficits and protein destabilization consistent with a loss-of-function mechanism |