| Item | Details | Key supporting citation IDs | URL |
|---|---|---|---|
| Causal mechanism | 2q37 deletion syndrome / BDMR is primarily a contiguous-gene deletion disorder in which **HDAC4 haploinsufficiency** is the main established driver of core features, especially brachydactyly type E, developmental delay/intellectual disability, and behavioral abnormalities. Williams et al. refined the BDMR critical region to **HDAC4** and identified de novo intragenic HDAC4 defects in non-deletion cases. (pqac-00000011, pqac-00000018) | (pqac-00000011, pqac-00000018) | https://doi.org/10.1016/j.ajhg.2010.07.011 |
| Key gene | **HDAC4** (2q37.3), a class IIa histone deacetylase and transcriptional corepressor interacting with factors including **MEF2C** and **RUNX2**; dosage sensitivity is central to the syndrome. Additional genes in larger deletions may modify expressivity, but HDAC4 has the strongest causal support. (pqac-00000011, pqac-00000027) | (pqac-00000011, pqac-00000027) | https://doi.org/10.1016/j.ajhg.2010.07.011 |
| CNV size range in recent cohort | In the 2023 nine-patient series, **MLPA** first detected the 2q37 deletion and **array-CGH** then defined deletion sizes ranging from **1.84 Mb to 8.14 Mb**. Four patients had pure 2q37 deletions; five had deletion/duplication rearrangements. (pqac-00000002) | (pqac-00000002) | https://doi.org/10.3390/genes14020465 |
| Variant types | Pathogenic lesion classes include **terminal or interstitial heterozygous deletions**, **complex unbalanced rearrangements**, **intragenic deletions/insertions disrupting HDAC4**, and rare **HDAC4 missense variants** associated either with classical BDMR-like disease or distinct HDAC4-related neurodevelopmental syndromes. (pqac-00000011, pqac-00000006, pqac-00000026) | (pqac-00000011, pqac-00000006, pqac-00000026) | https://doi.org/10.1016/j.ajhg.2010.07.011 |
| Familial interstitial deletion evidence | A three-generation familial interstitial 2q37.3 deletion was reported with coordinates **arr 2q37.3q37.3(239,395,957-240,154,599)x1** (approx. 800 kb), including **HDAC4, FLJ43879, and TWIST2**, confirmed by **array CGH and FISH**. This supports inherited disease in a minority of families. (pqac-00000012) | (pqac-00000012) | https://doi.org/10.1038/ejhg.2012.240 |
| Inheritance pattern | The disorder is generally considered **autosomal dominant** at the molecular level because a single heterozygous pathogenic deletion or HDAC4 defect is sufficient; however, **most 2q37.3 deletions are de novo**, with only a minority familial. Variable expressivity is documented in inherited cases. (pqac-00000012, pqac-00000014, pqac-00000006) | (pqac-00000012, pqac-00000014, pqac-00000006) | https://doi.org/10.1038/ejhg.2012.240 |
| Recommended first-line test | **Chromosomal microarray (array-CGH/CMA)** is the practical first-line molecular test for suspected 2q37 deletion syndrome because it detects pathogenic terminal/interstitial CNVs and defines size/content. The 2023 review states array-CGH is the **gold standard** for diagnosis. (pqac-00000005) | (pqac-00000005) | https://doi.org/10.3390/genes14020465 |
| Screening workflow used in 2023 study | The 2023 cohort used **MLPA subtelomeric screening (P036/P070 and P264 kits)** as an initial low-cost screen, followed by **CGH-array** confirmation for deletion size/location and detection of additional CNVs. This is a pragmatic workflow where subtelomeric deletion is suspected clinically. (pqac-00000002, pqac-00000005) | (pqac-00000002, pqac-00000005) | https://doi.org/10.3390/genes14020465 |
| Confirmatory / complementary tests | Complementary testing may include **karyotype** for visible rearrangements, **FISH** for confirming interstitial/terminal deletions, and **WES** when a BDMR phenotype is present but CNV testing is negative or equivocal, particularly to detect **intragenic HDAC4 variants**. (pqac-00000002, pqac-00000012, pqac-00000006) | (pqac-00000002, pqac-00000012, pqac-00000006) | https://doi.org/10.1297/cpe.2022-0076 |
| Breakpoint mapping evidence | Breakpoint/deletion mapping in AJHG 2010 showed the BDMR critical interval overlaps **HDAC4**, and expression studies demonstrated ~50% reduction of HDAC4 expression in deletion carriers involving HDAC4, supporting haploinsufficiency. A figure-based mapping summary specifically localizes the critical region to HDAC4. (pqac-00000018, pqac-00000019) | (pqac-00000018, pqac-00000019) | https://doi.org/10.1016/j.ajhg.2010.07.011 |
| HDAC4 missense example | A 2023 family report identified **HDAC4 NM_001378414.1:c.2204G>A (p.Arg735Gln)** by **whole-exome sequencing**, confirmed by Sanger sequencing. The variant was absent from major population databases, predicted damaging, and classified as likely pathogenic; affected relatives had mild ID, short stature, mild cardiac anomalies, and some hypothyroidism. (pqac-00000001, pqac-00000006) | (pqac-00000001, pqac-00000006) | https://doi.org/10.1297/cpe.2022-0076 |
| Tumor surveillance note | A 2024 AACR surveillance update lists **2p24 duplication/2q37 deletion** with **undefined Wilms tumor risk**; hepatoblastoma risk is not specified for this entry. The Wilms tumor surveillance recommendation is **“Shared decision”**, and the table notes that neuroblastoma concern/screening discussion should occur with families. This does **not** establish a routine evidence-based Wilms screening protocol specific to isolated 2q37 deletion syndrome. (pqac-00000008) | (pqac-00000008) | https://doi.org/10.1158/1078-0432.CCR-24-2100 |


*Table: This table summarizes the key molecular etiology and diagnostic evidence for 2q37 deletion syndrome/BDMR, emphasizing HDAC4 haploinsufficiency, typical CNV findings, inheritance patterns, and current testing strategies. It also includes a recent tumor-surveillance note relevant to counseling and follow-up.*