Research & Findings

Kim et al. · American Journal of Medical Genetics, 2026 (epub 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.

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.

Published 2025 · 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).

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.

Sashiyama et al. · iScience, May 2025 · PubMed

What was studied: Researchers investigated how ANKRD11 (the protein mutated in KBG syndrome) interacts with SETD5 at the molecular level, specifically examining whether ANKRD11 affects SETD5 protein levels and the downstream effect on ribosomal RNA and protein production.

• ANKRD11 directly regulates the expression of SETD5 -- when ANKRD11 is reduced (as in KBG syndrome), SETD5 protein levels are also reduced.
• Both proteins together control levels of ribosomal RNA (rRNA) and the efficiency of cellular protein translation.
• This provides a specific molecular mechanism to explain why KBG syndrome and SETD5 Syndrome produce overlapping clinical features: both reduce SETD5 function, one directly (SETD5 mutation) and one indirectly (ANKRD11 mutation lowering SETD5 levels).
• This is a separate and complementary finding to the shared protein complex described in the 2025 bioRxiv preprint.

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 among the first published case reports documenting the prenatal phenotype of SETD5 Syndrome.
• 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.

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.

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.

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.

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.