| Test modality | Purpose | Key findings / performance | Real-world implementation notes | Key references with URL / date |
|---|---|---|---|---|
| Whole-exome sequencing (WES) / broader NGS | Detect germline pathogenic ATRX variants in suspected ATR-X syndrome or related ATRX-associated neurodevelopmental phenotypes | WES identified a novel frameshift ATRX variant in a child with ATRX-related disease; the 2024 review/case synthesis notes ATR-X syndrome and MRXHF1 are caused by ATRX pathogenic variants, with missense variants most common overall and ADD/helicase domains frequently affected (pqac-00000000, pqac-00000028) | Practical first-line molecular test in rare disease workups; useful when phenotype includes intellectual disability, hypotonia, craniofacial features, genital anomalies, GI disease, seizures, or anemia/alpha-thalassemia; variants are typically classified with ACMG criteria and may require segregation/orthogonal confirmation (pqac-00000000) | Wang et al., *BMC Pediatrics* (Oct 2024), https://doi.org/10.1186/s12887-024-05088-0 (pqac-00000000, pqac-00000028) |
| Whole-genome sequencing (WGS) / structural-variant-capable sequencing | Detect SNVs plus structural or intragenic ATRX variants that may be missed or only partially resolved by targeted approaches | Long-read WGS-based workflows can simultaneously identify single-nucleotide and structural variants while also deriving methylation data; automated nanopore calling identified 18/19 SNVs in one developmental-disorders cohort, with one low-level mosaic variant requiring manual review (pqac-00000008) | Particularly relevant when prior exome/panel testing is negative, when a CNV/deletion is suspected, or when integrated genomic + epigenomic resolution is needed for interpretation; still emerging rather than universal standard of care for ATRX syndrome (pqac-00000008, pqac-00000010) | Geysens et al., *medRxiv* (Apr 2024), https://doi.org/10.1101/2024.04.19.24305959; Mizuguchi et al., *Clinical Epigenetics* (Feb 2025), https://doi.org/10.1186/s13148-025-01832-0 (pqac-00000008, pqac-00000010) |
| DNA methylation episignature testing (EpiSign / array-based episignature workflow) | Functional support for diagnosis and variant interpretation, especially VUS resolution in ATRX-related neurodevelopmental disease | In a 97-case NDD series, expected episignatures were observed in 53/59 validation cases (90% overall), and ATRX-associated methylation profiling helped identify an ATRX-related diagnostic case in the test cohort (pqac-00000011) | Useful as a second-line functional assay after sequencing when phenotype is compatible but variant classification remains uncertain; can complement genomic findings and improve interpretation of ATRX deletions or uncertain variants (pqac-00000011) | Trajkova et al., *Human Genetics and Genomics Advances* (Jul 2024), https://doi.org/10.1016/j.xhgg.2024.100309 (pqac-00000011) |
| Independent episignature validation for ATRX signature | Assess diagnostic accuracy / readiness for clinical use of published ATRX episignatures | Independent validation across ten NDD episignatures reported 100% specificity overall for the procedure, and the ATRX episignature showed 100% sensitivity in that dataset (pqac-00000009) | Supports real-world diagnostic confidence for ATRX methylation testing relative to several less robust signatures; authors still caution that broader validation and clear validity boundaries remain important before overgeneralization (pqac-00000009) | Husson et al., *European Journal of Human Genetics* (Oct 2024), https://doi.org/10.1038/s41431-023-01474-x (pqac-00000009) |
| Nanopore long-read sequencing with integrated episignature detection | Simultaneous genetic and epigenetic testing in a single assay | In a proof-of-concept developmental-disorders cohort, SVM classifiers recognized an episignature and assigned the correct disease in 17/20 patients, while all healthy controls were classified as controls; the approach also showed how ATRX episignature information can help classify an ATRX variant as benign in a complex case (pqac-00000008) | Consolidates what is often a multi-step workflow (variant detection, CNV/SV analysis, methylation profiling, and in some settings X-inactivation assessment) into one platform; promising for specialized clinical genetics laboratories, but currently best viewed as advanced/early implementation rather than routine everywhere (pqac-00000008) | Geysens et al., *medRxiv* (Apr 2024), https://doi.org/10.1101/2024.04.19.24305959 (pqac-00000008) |
| Nanopore long-read methylome profiling specifically including ATR-X syndrome cases | Define long-read DNA methylation signatures unique to ATR-X syndrome and potentially raise diagnostic yield | Sequencing of seven ATR-X syndrome cases and 22 controls enabled extraction of ATR-X-specific long-read DNA methylation signatures as alternatives to array-derived episignatures; authors argue simultaneous genetic and epigenetic evaluation may improve discovery and diagnostic yield (pqac-00000010) | Relevant for future integrated diagnostics and for laboratories interested in replacing sequential array + sequencing workflows with one assay; ATRX-specific sensitivity/specificity values were not provided in the retrieved excerpt (pqac-00000010) | Mizuguchi et al., *Clinical Epigenetics* (Feb 2025), https://doi.org/10.1186/s13148-025-01832-0 (pqac-00000010) |


*Table: This table summarizes current diagnostic modalities for ATRX syndrome, spanning standard genomic sequencing and newer DNA methylation episignature approaches. It highlights recent validation and implementation data that are useful for clinical interpretation, especially when variants are uncertain.*