| Knowledge-base field | Evidence status | Concise finding | Key evidence |
|---|---|---|---|
| Disease identity | Established disease-level classification | **Intellectual disability, autosomal dominant 34 (MRD34)**; the expanded phenotype is termed **ceramide transporter (CerTra) syndrome**. | OMIM **616351**; MONDO **MONDO:0014599**. Synonyms include *autosomal dominant mental retardation 34* and *CERT1-related intellectual disability*. (pqac-00000001, pqac-00000003, pqac-00000005) |
| Gene and locus | Established human genetic evidence | Heterozygous variants in **CERT1** (historical symbol **COL4A3BP**; aliases **CERT** and **GPBP**), encoding ceramide transporter 1; locus **5q13**; Ensembl **ENSG00000113163**. | OMIM gene **604677**; Open Targets identifies a definitive monoallelic association. (pqac-00000000, pqac-00000002, pqac-00000003) |
| Inheritance | Established human genetic evidence | **Autosomal dominant**, usually caused by a de novo heterozygous missense variant. In the largest cohort, 25/27 informative variants (**93%**) were de novo. | Gehin et al., May 15, 2023, DOI: [10.1172/JCI165019](https://doi.org/10.1172/jci165019); PMID **36976648**. (pqac-00000005, pqac-00000008) |
| Strongest cohort | Established human cohort evidence | The 2023 study analyzed **31 unrelated individuals with 22 distinct CERT1 missense variants**, including 18 reportedly novel variants. Most variants, 27/31 (**87%**), occurred between the PH and C-terminal START-related domains. | Gehin et al., 2023, DOI: [10.1172/JCI165019](https://doi.org/10.1172/jci165019). (pqac-00000004, pqac-00000005) |
| Developmental phenotype | Established human cohort evidence | **Motor delay occurred in 26/29** evaluable individuals; only 4/26 (**15%**) lacked developmental delay by the end of the first year. Intellectual disability ranged from mild to profound, with frequent severe speech impairment. | Gehin et al., 2023. (pqac-00000004, pqac-00000009) |
| Behavioral phenotype | Established human cohort evidence | Autism spectrum disorder occurred in **19/27 (70%)** evaluable individuals. Stereotypies, self-injury, ADHD, anxiety, aggression, sleep disruption, and increased pain tolerance were also reported. | Gehin et al., 2023; earlier reports described anxiety and self-mutilation. (pqac-00000002, pqac-00000004) |
| Neurologic phenotype | Established human cohort and case evidence | Seizures occurred in **16/29** evaluable individuals. Other findings included infantile hypotonia, thin or hypoplastic corpus callosum, ventriculomegaly, delayed myelination, cerebral or cerebellar atrophy, and leukodystrophy-like changes. | Gehin et al., 2023; Murakami et al., December 21, 2020, DOI: [10.1371/journal.pone.0243980](https://doi.org/10.1371/journal.pone.0243980); PMID **33347465**. (pqac-00000006, pqac-00000017) |
| Variant hotspots | Established human genetic evidence | Variants cluster at **p.S132, p.S135, p.S138, and p.S141** in the serine-repeat motif; **p.T166**; **p.D240, p.G243, p.T247, and p.T251**; and **p.V326F, p.A329P, p.L330V, and p.L330P** near the FFAT motif. | p.S132/p.S135 variants were associated with more severe presentations, although genotype groups were small. (pqac-00000004, pqac-00000017) |
| Variant-interpretation caution | Established segregation and functional evidence | Not every rare CERT1 variant is causal. **c.2242_2243dupAA; p.(Pro749fs)** was inherited and did not reproduce abnormal activity in functional testing, so it was judged noncausative in that family. | Tamura et al., October 22, 2021, DOI: [10.1016/j.jbc.2021.101338](https://doi.org/10.1016/j.jbc.2021.101338); PMID **34688657**. (pqac-00000007, pqac-00000018) |
| Molecular mechanism | Demonstrated in biochemical and cellular models; clinical consequences partly inferred | CERT transfers ceramide from the **endoplasmic reticulum to trans-Golgi contact sites** for sphingomyelin synthesis. Disease variants impair phosphorylation-dependent autorepression or another regulatory domain, causing **gain of function**, excessive ceramide transport, altered sphingolipid flux, and abnormal punctate localization. | Murakami et al., 2020; Tamura et al., 2021; Gehin et al., 2023. (pqac-00000005, pqac-00000007, pqac-00000008, pqac-00000019) |
| Diagnostic approach | Current clinical-genetics practice; no formal disease-specific criteria | Use an intellectual-disability or neurodevelopmental gene panel, preferably trio **WES/WGS**, with parental segregation and transcript-specific HGVS reporting. Apply ACMG/AMP criteria and interpret variants using population frequency, clustering, segregation, and functional evidence. MRI and EEG characterize complications but are not diagnostic biomarkers. | Published cohorts used exome sequencing, segregation analysis, ACMG interpretation, neurologic assessment, MRI, and EEG. (pqac-00000013, pqac-00000014, pqac-00000018) |
| Treatment status | No established disease-modifying human treatment | Care is supportive and individualized: developmental intervention, speech or augmentative communication, occupational and physical therapy, behavioral and sleep support, feeding care, and standard antiseizure treatment when required. No validated genotype-guided therapy or disease-specific interventional trial was identified. | Human reports provide no efficacy or safety evidence for CERT1-directed treatment. (pqac-00000013, pqac-00000014, pqac-00000015) |
| Experimental therapy | Preclinical only | The CERT inhibitor **HPA-12** corrected locomotor and morphological abnormalities in a Drosophila model. This supports therapeutic plausibility but provides no human efficacy, safety, or dosing evidence. | Gehin et al., 2023. (pqac-00000015, pqac-00000016) |
| Model-organism evidence | Experimental Drosophila evidence | CERT gain of function in **Drosophila melanogaster** caused abnormal head or brain size and locomotor hypoactivity; pharmacologic rescue supports excessive CERT activity as the disease mechanism. | Gehin et al., 2023, DOI: [10.1172/JCI165019](https://doi.org/10.1172/jci165019); PMID **36976648**. (pqac-00000005, pqac-00000008, pqac-00000016) |
| Epidemiology | Major evidence gap | Prevalence, incidence, carrier frequency, founder effects, geographic enrichment, and sex ratio have not been established. Published cases are rare-disease referrals rather than a population-based cohort. | The largest available delineation included 31 unrelated individuals, without a population denominator. (pqac-00000004, pqac-00000005) |
| Prognosis | Major evidence gap | The condition is chronic and lifelong with variable severity. Developmental slowing or regression may occur, and one severely affected adult had progressive leukodystrophy-like MRI changes. Survival, life expectancy, mortality, quality-of-life scores, and prognostic biomarkers remain unknown. | Human cohort and longitudinal single-case observations. (pqac-00000006, pqac-00000017) |


*Table: Concise evidence summary for CERT1-related CerTra syndrome, covering identity, genetics, cohort statistics, phenotype, mechanism, diagnosis, treatment, models, and major knowledge gaps. Evidence is explicitly distinguished as established human, experimental, inferred, or unavailable.*