Research & Findings

Fernandez Garcia et al.  ·  Nature Neuroscience, April 2026  ·  Read article

What was studied: Researchers at Yale University and the Icahn School of Medicine used CRISPR gene editing to knock out 23 neurodevelopmental disorder (NDD) genes -- including SETD5 -- in human stem cell-derived brain cells. The goal was to find out whether these different genes, which cause different NDD diagnoses, affect the same underlying biological pathways.

• SETD5 was one of 23 NDD loss-of-function genes specifically targeted and studied; the paper focuses on all 23 genes collectively, not SETD5 alone.
• The study found the greatest degree of overlap across all 23 genes in mature glutamatergic neurons, the primary excitatory signaling cells in the brain.
• Shared pathways across the gene set included synaptic function, epigenetic regulation, and mitochondrial function -- the last of which was unexpected and consistent with separate SETD5 research showing mitochondrial involvement.
• Drugs that reversed the shared molecular signatures in the cell models also improved behavioral phenotypes in zebrafish carrying NDD gene mutations, suggesting the convergent pathways may be therapeutically relevant.
• This is the first study to examine SETD5 alongside other NDD genes in human iPSC-derived neurons using a standardized CRISPR approach, providing directly comparable data across conditions.

Northrup et al. · Genetics in Medicine Open, 2026 · Read article

What was studied: Researchers at UTHealth Houston surveyed 51 members of the SETD5-related disorder Facebook support group (August–November 2024) to document a broader range of medical features reported by families, and to describe how the online community supports affected families.

• Respondents represented individuals from 12 countries; 80% of affected individuals were under 18, with a mean age of diagnosis of 9.2 years.
• Most common features reported in this study: developmental delay (96%), hypotonia (78%), intellectual disability (75%), gait abnormality (59%), vision problems (51%), constipation (47%), and anxiety (47%).
• Pain-related features were reported for the first time in the published literature using family data: high pain tolerance (43%), persistent leg pain (31%), and joint pain (27%).
• Families reported that the Facebook support group was a primary source of information about therapies, school accommodations, and advocacy.

Kim et al. · American Journal of Medical Genetics Part A, March 2026 · Published online October 2025 · PubMed

What was studied: Researchers re-evaluated a group of patients who had been diagnosed with Noonan syndrome but whose standard genetic testing was negative for RASopathy genes. Using expanded sequencing, they identified the true genetic cause in several patients.

• Six patients with features clinically consistent with Noonan syndrome were found to carry pathogenic SETD5 variants, not RASopathy mutations.
• SETD5 Syndrome can present with facial features, developmental delay, and other characteristics that overlap with Noonan syndrome, leading to initial misdiagnosis.
• This finding emphasizes that a Noonan-like appearance does not confirm a RASopathy and that comprehensive genetic sequencing is important.
• A correct genetic diagnosis can support access to condition-specific resources, registries, and research relevant to SETD5 Syndrome.

Heidargholizadeh et al. · Pediatric International, January 2026 · PubMed

What was studied: A team used whole exome sequencing to identify novel candidate genes in patients with congenital diaphragmatic hernia (CDH), a birth defect in which the diaphragm does not close completely, allowing abdominal organs to push into the chest cavity.

• SETD5 variants were identified in CDH patients through exome sequencing, implicating it as a candidate gene for this structural birth defect.
• This is an early-stage genetic association; a causal role for SETD5 in CDH has not been established.
• The finding extends the range of structural anomalies that may be associated with SETD5 variants, beyond previously documented features.

Rangel-Méndez et al.  ·  Molecular Syndromology, February 2026  ·  Read article   |   Dai et al.  ·  Molecular Genetics & Genomic Medicine, 2020  ·  PubMed

What was studied: Most published SETD5 cases involve de novo deletions or point mutations. Two papers add to the smaller body of literature on CNV gains (duplications) at 3p25 and on inherited SETD5-region losses.

• Rangel-Méndez et al. 2026: A 21-year-old with mild intellectual disability and late diagnosis was found to carry a 3p26.3–3p25.2 microduplication encompassing SETD5. The authors reviewed the literature on 3p25 duplications and found the evidence base is thin — only a small number of cases have been described.
• The phenotype associated with SETD5 duplication appears milder than haploinsufficiency in reported cases, though the literature is too limited to draw firm conclusions.
• Dai et al. 2020: Two sisters with intellectual disability, short stature, and microcephaly were found to carry a 3p26.3–3p25.3 deletion inherited from a mother with a balanced translocation between chromosomes 3 and 14.
• The mother — who carried the translocation in balanced form — had a history of recurrent miscarriage, illustrating that a balanced translocation involving the SETD5 region can be passed through generations with different outcomes depending on how it segregates.
• Both papers extend the documented range of 3p25 CNV types beyond de novo deletions.

Koparir et al. · Clinical Epigenetics, April 2026 · PubMed

What was studied: Researchers expanded the EpiSign library, a clinical diagnostic tool that identifies characteristic DNA methylation patterns (episignatures) associated with genetic syndromes caused by genes involved in chromatin regulation. SETD5 was among the conditions newly profiled.

• A blood-based DNA methylation episignature specific to SETD5 Syndrome was identified and validated, adding SETD5 to the growing list of conditions detectable through the EpiSign clinical test.
• Episignatures can serve as a functional test to help classify variants of uncertain significance (VUS) -- a DNA change that cannot be confirmed as disease-causing based on sequence analysis alone.
• Because SETD5 regulates chromatin structure, its loss-of-function leaves a detectable chemical imprint on the genome that persists in blood cells and can be measured in a clinical laboratory.

Callahan et al. · Clinical Genetics, 2025; 108(3):279–291 · PubMed

What was studied: Researchers used the National Brain Gene Registry to identify and analyze 13 individuals with SETD5 Syndrome, aged 2 to 37 years. The study documented genetic variants and clinical features, including features not previously described in the literature.

• Brain structural differences were identified in some participants, a feature not well-documented in prior SETD5 studies.
• Musculoskeletal problems were documented at higher rates than previously reported.
• 11 unique pathogenic or likely pathogenic variants were identified: 6 nonsense, 4 frameshift, 1 splice site.
• Symptom presentation varied substantially across participants, including those with similar mutations.

Burnett et al. · PLoS Biology, 2024; 22(6):e3002668 · PubMed

What was studied: Researchers compared behavioral impairments across multiple different genetic mouse models of autism, including Setd5 haploinsufficient mice, to identify shared features that may point to common underlying mechanisms.

• Setd5 haploinsufficient mice showed impairments in visual perception and place avoidance behavior -- difficulties that were shared across multiple different autism gene models.
• These shared behavioral impairments were driven by hypoexcitability (reduced neural activity) in the periaqueductal grey, a brainstem region involved in sensory processing and defensive behaviors.
• The finding that different autism-associated genes -- including SETD5 -- converge on the same brain circuit suggests potential shared therapeutic targets across multiple genetic forms of autism.
• Published in PLoS Biology, a high-impact open-access journal, making the findings freely available to the research community.

De Falco et al. · European Journal of Paediatric Neurology, 2024; 54:8–17 · PubMed

What was studied: A multicenter European team reported on 28 SETD5 Syndrome patients not previously described in any publication. The study focused specifically on neurological and psychiatric features.

• 75% of patients had intellectual disability or global developmental delay; 21% had borderline intellectual functioning; 3.6% had normal IQ.
• Autism spectrum disorder was confirmed in 24% of patients.
• Abnormal gait, including tip-toe walking, was documented in 36% of patients.
• Hyperkinetic or repetitive movements were documented in 21% of patients.
• Epilepsy was present in 14% of patients, across multiple seizure types.
• Neurological and psychiatric features co-occurred in multiple patients.

MDPI Genes, 2025; 16(8):859 · Read article

What was studied: Clinicians published a case report of a child with SETD5 overlap syndrome who was treated with recombinant human growth hormone (rhGH) for documented short stature.

• The child showed significant growth improvement following initiation of growth hormone therapy.
• This is the first published report of growth hormone treatment in any patient with SETD5 or SETD5 overlap syndrome.
• Short stature is a recognized feature of SETD5 Syndrome; prior to this report, no treatment data had been published.

Alessi et al. · Journal of Child Neurology, November 2025; 40(10):915–918 · PubMed

What was studied: Clinicians described a 6-year-old child with a confirmed pathogenic SETD5 variant who developed an epilepsy presentation not previously documented in association with SETD5 Syndrome.

• The seizure pattern in this child had not been previously documented in the SETD5 literature.
• This case extends the known range of epilepsy presentations associated with SETD5 Syndrome.
• Approximately 14% of patients had epilepsy in the largest published SETD5 Syndrome cohort (De Falco et al. 2024, 28 patients).

Sashiyama et al.  ·  iScience 28(7):112699, 2025  ·  PubMed  ·  Earlier bioRxiv preprint

What was studied: Researchers investigated why mutations in SETD5, ANKRD11 (KBG syndrome), and TBLR1 produce overlapping clinical features. They identified a shared molecular complex in brain cells that all three proteins participate in.

• The proteins produced by SETD5, ANKRD11, and TBLR1 form a single molecular complex in brain cells, called the SET3-like complex.
• TBLR1 functions as a molecular bridge linking ANKRD11 and SETD5 to a larger regulatory complex called NCoR.
• This provides a molecular explanation for why mutations in these three genes produce similar clinical features.
• The NCoR complex has been studied as a therapeutic target in other disease contexts.

Dams et al. · Brain Circulation, April 2025 · Read article

What was studied: The authors report a patient with a confirmed pathogenic heterozygous SETD5 variant who was subsequently diagnosed with moyamoya syndrome -- a progressive narrowing of major blood vessels in the brain that increases risk of stroke.

• This is only the second published case linking a SETD5 variant to moyamoya syndrome, following the Pinard et al. 2019/2020 report.
• The patient's presentation underscores that moyamoya, while rare, can occur in SETD5 Syndrome and may not be identified without neurological investigation.
• The authors discuss the possible mechanism by which SETD5 haploinsufficiency could contribute to abnormal blood vessel development in the brain.

Fan et al. · Birth Defects Research, December 2025 · PubMed

What was studied: Clinicians described a fetus identified prenatally with a SETD5 mutation, documenting which features were detectable before birth through ultrasound and genetic testing, and reviewing the existing published literature on prenatal presentations of SETD5 Syndrome.

• This is one of a small number of published case reports documenting the prenatal phenotype of SETD5 Syndrome; an earlier case involving first-trimester cystic hygroma was described by Pan et al. in 2020.
• The case documents that some SETD5-associated features may be identifiable on prenatal ultrasound, contributing to earlier diagnosis pathways.
• The authors reviewed existing SETD5 literature in the context of prenatal genetic counseling.

Rivera-Munoz et al. · European Journal of Human Genetics, December 2025 · PubMed

What was studied: A large clinical exome sequencing study examined patients with congenital anomalies of the kidney and urinary tract (CAKUT) accompanied by additional clinical features. The goal was to identify genetic causes and expand the known phenotypic range of relevant genes.

• SETD5 was identified as a gene associated with increased risk of congenital kidney and urinary tract anomalies in this dataset.
• This links SETD5 to a new organ system -- the urinary tract -- not prominently documented in prior SETD5 literature.
• This is an association finding from a broader genetic sequencing study, not a targeted SETD5 investigation.

Ansari et al. · Human Mutation, January 2025 · PubMed

What was studied: Researchers performed whole-genome sequencing on a cohort of patients referred for clinical evaluation of Cornelia de Lange Syndrome (CdLS), a rare genetic disorder that shares features with several other conditions. The goal was to identify the genetic cause in patients where standard targeted testing was negative or inconclusive.

• Pathogenic SETD5 variants were identified in a subset of patients in this CdLS cohort, contributing to the documented phenotypic overlap between SETD5 Syndrome and CdLS.
• The finding extends the list of conditions that may be initially suspected before a SETD5 Syndrome diagnosis is reached, alongside previously documented overlaps with Noonan syndrome, KBG syndrome, and others.
• Whole-genome sequencing identified genetic causes in patients where targeted panel testing had not provided a diagnosis.

Oguri et al. · European Journal of Medical Genetics, 2025 · PubMed

What was studied: Researchers analyzed epilepsy features and EEG (electroencephalogram) findings in patients with 3p deletion syndrome, a chromosomal condition whose deletions can encompass the SETD5 gene region depending on size and location.

• The study documented epilepsy types, seizure frequencies, and characteristic EEG patterns observed in patients with 3p chromosomal deletions.
• Patients whose deletions encompassed the SETD5 region were included in the analysis, contributing clinical data on seizure profiles in this subset.
• The paper adds to the neurological characterization of the 3p25 chromosomal region and the conditions associated with it.

Gabellini et al. · International Journal of Molecular Sciences, 2022; 24(1):167 · PubMed

What was studied: Researchers used CRISPR/Cas9 gene editing to completely inactivate the setd5 gene in zebrafish and observed the resulting behavioral effects, with a focus on social behavior relevant to autism.

• Complete CRISPR-induced inactivation of setd5 in zebrafish led to measurable social impairments, consistent with autism-like behavioral changes.
• This study extends the zebrafish model of SETD5 first established by Sessa et al. 2019, using a more precise gene-editing approach (CRISPR/Cas9 rather than morpholino knockdown).
• The zebrafish model continues to be validated as a platform for studying SETD5-related social behavior and for screening potential therapeutic compounds.

Pascolini et al. · American Journal of Medical Genetics Part A, May 2022; 188(5):1623–1625 · PubMed

What was studied: Italian clinicians described a child with a confirmed pathogenic SETD5 variant whose facial features and clinical presentation closely resembled KBG syndrome, expanding the known overlap between the two conditions.

• The child carried a pathogenic SETD5 variant but presented with features that strongly suggested KBG syndrome at first clinical evaluation.
• The case adds to a growing set of reports documenting that SETD5 Syndrome and KBG syndrome can be clinically indistinguishable in some children.
• The authors describe additional novel features in the child that further refine the published SETD5 phenotype.

European Journal of Pediatrics, 2023 · Read article

What was studied: Researchers enrolled 214 patients with short stature and multi-organ abnormalities and performed whole exome sequencing (WES) to identify variants in epigenetic modification genes. SETD5 was one of 19 genes identified across the cohort.

• WES identified pathogenic or likely pathogenic variants in 33 of 214 patients (15.4%), across 19 epigenetic genes including SETD5.
• Webbed neck was reported in association with a SETD5 variant for the first time in published literature.
• Across all 33 patients (representing 19 epigenetic genes, including but not limited to SETD5), common overlapping features included developmental delay or intellectual disability (93.9%), small hands (42.4%), clinodactyly of the 5th finger (42.4%), long eyelashes (39.4%), and hearing impairment (27.3%). These percentages reflect the full multi-gene group, not SETD5 patients specifically.
• 19 of the 33 variants identified had never been previously reported.
• The study documents that SETD5 shares clinical overlap with other epigenetic modification disorders including KMT2A, KMT2D, ANKRD11 (KBG syndrome), and Cornelia de Lange syndrome genes.

Zaghi et al. · Molecular Autism, 2023; 14:20 · Read article

What was studied: Human neural cells with SETD5 haploinsufficiency were created in the laboratory and analyzed to measure the effects on mitochondria (the structures inside cells responsible for producing energy).

• Brain cells with SETD5 haploinsufficiency showed fragmented mitochondria compared to cells with normal SETD5 function.
• Fragmented mitochondria produced less ATP (the molecule cells use to power activity) compared to normal cells.
• Reduced cellular energy production in neurons may contribute to cognitive and behavioral symptoms associated with SETD5 Syndrome.
• Mitochondrial function is identified as a specific cellular mechanism that could potentially be targeted therapeutically.

Nakagawa et al. · Frontiers in Genetics, 2023 · PubMed

What was studied: Mouse models carrying either SETD5 or KBG syndrome (ANKRD11) mutations were studied side by side to identify shared neurological mechanisms.

• Mice with SETD5 mutations showed learning impairments and behavioral differences consistent with autism-like features.
• Both SETD5 and KBG mutant mice showed disruption to the same neurological pathway.
• These findings support the clinical observation of overlapping features between SETD5 and KBG syndrome.

Iwagawa et al. · FEBS Letters, 2023

What was studied: Researchers examined the retina (the light-sensitive tissue at the back of the eye) in models lacking normal SETD5 function.

• SETD5 was found to be required for normal survival and proliferation of retinal cells during development.
• In the absence of functional SETD5, retinal cell death increased and cell proliferation was reduced.
• This is the first published study documenting a role for SETD5 in eye development.

ESPE 2023 · Conference abstract conf. abstract

What was presented: Additional cases of reduced bone mineral density and vertebral fractures in SETD5 Syndrome patients were presented at the European Society for Pediatric Endocrinology annual conference.

• These cases extend and confirm the bone fragility association first published in 2021.
• Vertebral compression fractures were documented in patients, including cases with no clear injury event.
• Presentation at a pediatric endocrinology conference increases awareness among specialists who treat children with growth and bone conditions.

Ahsan et al. · Pediatric Neurology, January 2023; 138:25–26 · PubMed

What was studied: Clinicians at Children's Hospital Los Angeles described a patient with a novel pathogenic SETD5 variant who presented with two clinical features not previously documented in association with SETD5 Syndrome.

• The patient had pigmentary retinopathy (a vision-affecting eye condition) and central hypothyroidism, neither of which had been previously reported in published SETD5 Syndrome cases.
• Other features documented included autism, stuttering, brachycephaly, low-set ears, synophrys, ptosis, depressed nasal bridge, thin upper lip, micrognathia, postaxial polydactyly, leg-length discrepancy, feeding difficulties, congenital heart defects, and behavioral challenges.
• The authors note that they cannot definitively confirm whether the retinopathy and hypothyroidism are caused by SETD5, but the case expands the documented genotypic and phenotypic spectrum of the condition.

Manokaran et al. · Seizure: European Journal of Epilepsy, November 2023; 112:109–111 · PubMed · Read article

What was studied: Clinicians from The Hospital for Sick Children (Toronto) described a 15-year-old girl with mild intellectual disability and a confirmed pathogenic SETD5 variant who developed drug-resistant focal epilepsy at age 9.

• The patient developed focal seizures at age 9 that did not respond to multiple antiseizure medications.
• Inter-ictal EEG (between seizures) showed sleep-activated right occipito-temporal spike/sharp waves; ictal EEG (during seizures) showed right occipital localization.
• Over approximately four years from seizure onset, EEG abnormalities became more right hemispheric and then generalized, possibly representing secondary bilateral synchrony.
• The authors note that the current understanding of SETD5's role in epilepsy is limited, with most published SETD5 data coming from neurodevelopmental rather than epilepsy studies.

Li et al.  ·  Frontiers in Endocrinology, March 2023; 14:1089527  ·  PubMed

What was studied: This review article synthesizes the published research on SETD5 as a gene — covering its protein structure, what it actually does inside cells, how haploinsufficiency leads to neurodevelopmental disorders, why SETD5 overexpression appears in some cancers, and how it is regulated through the ubiquitin-proteasome system.

• SETD5 encodes a protein in the lysine methyltransferase family, but research has shown it functions primarily as a scaffold — organizing other regulatory proteins — rather than as an active enzyme directly methylating histones.
• The review covers the full range of evidence for SETD5's role in NDD, including mouse model data, human patient studies, and molecular mechanism research available through early 2023.
• It describes how SETD5 protein levels are controlled by the ubiquitin-proteasome system, which is relevant to understanding why haploinsufficiency (having one functional copy) cannot easily be compensated for by the remaining copy.
• The paradox between SETD5 loss causing neurodevelopmental disorder and SETD5 overexpression appearing in multiple cancer types is discussed, with SETD5's roles in each context described separately.

Anderson et al. · Clinical Genetics, 2021 · Read article

What was studied: A patient with SETD5 Syndrome presented with multiple vertebral fractures and significantly below-average bone mineral density for their age. The authors reviewed existing SETD5 literature to assess how often bone-related features had been documented.

• This is the first published paper formally linking SETD5 to bone fragility.
• The patient had vertebral wedge fractures (compression deformities of the spinal vertebrae) and reduced bone mineral density on DEXA scan.
• Treatment with zoledronic acid, a bone-strengthening medication, improved bone density measurements in this patient.
• The authors of this study suggested bone density evaluation for all patients with SETD5 Syndrome; families may wish to discuss this with their child's care team.

Cheung et al. · Genesis, 2021; 59(7–8):e23421 · PubMed

What was studied: Researchers used mouse models to investigate the role of Setd5 in heart development, specifically in the cardiopharyngeal mesoderm (the tissue that gives rise to the heart and certain head/neck structures).

• Setd5 was shown to be required for normal development of the cardiopharyngeal mesoderm -- the precursor tissue for both heart structures and certain facial/neck muscles.
• Setd5 haploinsufficiency was associated with outflow tract defects in the mouse heart, providing a biological explanation for congenital heart defects observed in SETD5 patients.
• This is the first study to provide a specific developmental mechanism connecting SETD5 to cardiac malformations.

Pan et al.  ·  Taiwanese Journal of Obstetrics and Gynecology, November 2020  ·  PubMed

What was studied: Clinicians described a pregnancy in which first-trimester ultrasound identified cystic hygroma. Standard chromosomal microarray returned normal results, and subsequent ultrasound was also normal. Whole-exome sequencing later identified a SETD5 frameshift variant (c.646delC) as the cause.

• This is among the earliest published prenatal cases in which SETD5 Syndrome was confirmed as the underlying diagnosis after a first-trimester ultrasound finding.
• Standard microarray testing was normal, illustrating that SETD5 point variants and small frameshift variants may not be detected by chromosomal microarray alone — only by sequencing-based approaches.
• The cystic hygroma resolved on follow-up ultrasound; the SETD5 variant was identified only after WES was performed.
• The authors note that cystic hygroma in the first trimester, even with normal microarray results, may warrant further sequencing investigation when the fetus is otherwise structurally normal.

Pires et al. · Pediatric Blood & Cancer, 2020 · Read article

What was studied: Clinicians described a 2-year-old girl with a de novo 125-kb 3p25.3 microdeletion encompassing SETD5 who developed low-stage neuroblastoma (ganglioneuroblastoma intermixed variant, stage L1). The authors reviewed existing SETD5 and neuroblastoma literature to explore a possible biological connection.

• This is the first published case reporting neuroblastoma in a child with confirmed SETD5 haploinsufficiency.
• The patient presented with classic SETD5/3p25 features including low frontal hairline, synophrys, long eyelashes, epicanthal folds, camptodactyly, delayed psychomotor development, intellectual disability, and agitated behavior.
• The deletion narrowed the critical overlapping 3p25 region to 25 kb, containing only the 3' end of SETD5 -- reinforcing SETD5 as the single gene responsible for the neurodevelopmental phenotype in 3p25 deletions.
• SETD5-haploinsufficient mice develop neural crest defect-associated features (craniofacial abnormalities, tooth displacement, eye problems) that overlap with features seen in SETD5 patients -- suggesting a possible shared biological basis between neurodevelopmental defects and neuroblastoma susceptibility.
• The authors conclude that SETD5 germline deletion may confer shared susceptibility to neurodevelopmental disorders and childhood cancer, though larger studies are needed to confirm this.

Crippa et al. · Frontiers in Neurology, 2020; 11:631 · PubMed

What was studied: Clinicians described three patients who were initially clinically suspected of having KBG syndrome but were found through genetic testing to carry pathogenic SETD5 variants instead.

• All three patients had features overlapping with KBG syndrome, reinforcing the documented clinical similarity between the two conditions.
• Genetic testing revealed SETD5 haploinsufficiency rather than ANKRD11 mutations (the gene responsible for KBG syndrome).
• This study provided early clinical evidence for the molecular connection between SETD5 and the KBG syndrome pathway -- a link that has since been confirmed at the molecular level by Sashiyama et al. 2025.

Nakagawa et al. · iScience, 2020; 23(4):101030 · PubMed

What was studied: Researchers investigated how the SETD5 protein controls the growth and proliferation of neural cells by regulating ribosomal DNA (rDNA) -- the genes that produce the cell's protein-building machinery.

• SETD5 was shown to directly control neural cell proliferation through epigenetic regulation of rDNA expression.
• When SETD5 function is reduced, neural cell proliferation is altered -- providing a specific cellular mechanism linking SETD5 haploinsufficiency to brain developmental differences.
• The rDNA regulation pathway represents a distinct mechanism from the NCoR pathway identified by Deliu et al. 2018, suggesting SETD5 affects brain development through multiple biological pathways.

Wang et al. · Cancer Cell, 2020; 37(5):689–703 · PubMed   |   Yang et al. · Cancer Research, 2020 & 2022 · PubMed (2020)

What was studied: A body of research has examined SETD5 in the context of cancer biology. The most prominent studies focus on SETD5 overexpression in solid tumors -- including pancreatic, breast, and other cancers. These studies describe SETD5 acting as an oncogene (a gene that promotes tumor growth) when it is overproduced in cancer cells.

• Wang et al. (2020, Cancer Cell) found that SETD5 is overexpressed in pancreatic cancer and promotes tumor cell survival. This work is in the context of excess SETD5 protein in cancer cells -- the opposite of the SETD5 haploinsufficiency (reduced function) that causes SETD5 Syndrome.
• Yang et al. (2020, 2022) found elevated SETD5 expression in breast cancer samples and in cancer cell lines. Again, these studies describe too much SETD5, not too little.
• The apparent paradox -- SETD5 loss causes neurodevelopmental differences, while SETD5 overexpression is associated with cancer -- is consistent with how many genes involved in development and cell growth behave differently depending on context and cell type.
• There is no published evidence that germline SETD5 haploinsufficiency (the genetic basis of SETD5 Syndrome) predisposes individuals to cancer. The cancer-associated research involves somatic (acquired, not inherited) overexpression in tumor cells.