| Gene | Syndrome label(s) in sources | Inheritance noted | Example variants (HGVS) reported in evidence | Core molecular function/pathway | Key clinical features/imaging from evidence | Key sources with year and DOI URL |
|---|---|---|---|---|---|---|
| **RNF216** | Gordon Holmes syndrome (GHS); RNF216-related disorder; also reported with Huntington-like disease, 4H syndrome, congenital hypogonadotropic hypogonadism | Usually autosomal recessive/monogenic biallelic; oligogenic/digenic cases also reported with **OTUD4** and **SRA1** | c.1860_1861dupCT (p.Cys621SerfsTer56); c.2061G>A (splice); c.1549C>T (p.R517X); c.591_592insTG (p.Gln198CysfsTer43); c.2042C>T (p.P606L) | RBR-class **E3 ubiquitin ligase**; ubiquitin-proteasome/autophagy pathway; E3 activity depends on RBR domain + C-terminal extension | Core phenotype: hypogonadotropic hypogonadism, cerebellar ataxia, cognitive decline/dementia, chorea/other movement disorders; MRI: cerebellar and cortical atrophy, cerebral white-matter hyperintensities/leukoencephalopathy, thin posterior corpus callosum; some pituitary anomalies (hypoplastic posterior pituitary, partial empty sella) (pqac-00000019, pqac-00000020, pqac-00000021, pqac-00000022, pqac-00000023, pqac-00000024, pqac-00000026) | Rochtus 2024, https://doi.org/10.1210/jcemcr/luae195; Çelik 2023, https://doi.org/10.1186/s12920-023-01529-4; Kallupurakkal 2023, https://doi.org/10.1136/bcr-2023-256994; Alqwaifly 2016, https://doi.org/10.4081/ni.2016.6444; Calandra 2019, https://doi.org/10.1002/mdc3.12721; Wu 2022, https://doi.org/10.21203/rs.3.rs-1310364/v1 |
| **OTUD4** | GHS; RNF216/OTUD4 digenic form | Digenic/oligogenic with **RNF216** reported | Not specified in provided snippets | **Deubiquitinase**; disordered ubiquitination pathway | Included in GHS spectrum with ataxia, hypogonadotropic hypogonadism, dementia/cognitive decline; more severe phenotypes reported when combined with RNF216 dysfunction in source summaries (pqac-00000006, pqac-00000020, pqac-00000021, pqac-00000022, pqac-00000025) | Margolin 2013, https://doi.org/10.1056/NEJMoa1215993; Alqwaifly 2016, https://doi.org/10.4081/ni.2016.6444; Wu 2022, https://doi.org/10.21203/rs.3.rs-1310364/v1 |
| **STUB1** (*CHIP*) | GHS; SCAR16/STUB1-related multisystemic neurodegeneration | Autosomal recessive/biallelic in reported GHS cases | c.737C>T (p.Thr246Met); c.194A>G (p.Asn65Ser); c.82G>A (p.Glu28Lys); c.430A>T (p.Lys144Ter) | Co-chaperone/**E3 ubiquitin ligase** in protein quality control/homeostasis | Cerebellar ataxia with hypogonadotropic hypogonadism; dysarthria, gaze-evoked nystagmus, severe dementia/cognitive impairment in some families; MRI: remarkable cerebellar atrophy; pituitary responsive to GnRH in reported sisters; broader multisystemic features can include spastic tetraparesis, epilepsy, autonomic dysfunction (pqac-00000000, pqac-00000016, pqac-00000017, pqac-00000018) | Shi 2014, https://doi.org/10.1093/hmg/ddt497; Hayer 2017, https://doi.org/10.1186/s13023-017-0580-x; Heimdal 2014, https://doi.org/10.1186/s13023-014-0146-0 |
| **PNPLA6** | Gordon Holmes syndrome (GH/GDHS); Boucher-Neuhauser syndrome (BNHS/BNS); also broader PNPLA6-related spectrum (SPG39, Oliver-McFarlane, Laurence-Moon) | Autosomal recessive/biallelic; often sibling cases; consanguinity common in several reports | c.3524C>G (p.Ser1175Cys); c.3323G>A (p.Arg1108Gln); c.3380C>G (p.Ser1127Cys); c.3847G>A (p.V1283M); c.3929A>T (p.D1310V) | Neuropathy target esterase (NTE); ER-localized **lysophospholipase/phospholipase esterase** | GHS/BNHS spectrum with cerebellar ataxia, hypogonadotropic hypogonadism, chorioretinal dystrophy/vision loss; additional features include peripheral axonal neuropathy, spasticity, growth hormone deficiency, cognitive impairment, vestibular areflexia; MRI often shows cerebellar atrophy, especially superior/dorsal vermis; progression may be slow with retained ambulation after long disease duration in some cohorts (pqac-00000008, pqac-00000009, pqac-00000010, pqac-00000011, pqac-00000012, pqac-00000013, pqac-00000014, pqac-00000015) | Nanetti 2022, https://doi.org/10.3389/fneur.2021.793547; Doğan 2021, https://doi.org/10.1080/13816810.2021.1894461; Liampas 2024, https://doi.org/10.1007/s11033-024-09515-4; Deik 2014, https://doi.org/10.1007/s00415-014-7516-3; Teive 2018, https://doi.org/10.1007/s12311-017-0909-y |
| **POLR3A / POLR3B / POLR1C** | 4H syndrome listed among ataxia-hypogonadism differential/overlap disorders | Not specified in provided snippets | Not specified in provided snippets | RNA polymerase III pathway (specific function not detailed in snippets) | Mentioned as genes associated with ataxia plus hypogonadism spectrum/4H overlap; no variant-level or imaging detail provided in the retrieved evidence snippets (pqac-00000021, pqac-00000022, pqac-00000024, pqac-00000026) | Calandra 2019, https://doi.org/10.1002/mdc3.12721; Wu 2022, https://doi.org/10.21203/rs.3.rs-1310364/v1; Kallupurakkal 2023, https://doi.org/10.1136/bcr-2023-256994 |


*Table: This table summarizes the principal genes implicated across the cerebellar ataxia–hypogonadism / Gordon Holmes syndrome spectrum, including inheritance models, representative variants, molecular functions, and phenotype/imaging findings supported by the retrieved evidence.*