A plain-language summary of published SETD5 Syndrome research, compiled by hand with the help of research tools. Every card links to its source.
Most recent
This report describes one boy, so one patient out of one. Exome sequencing found three rare variants in three different genes. One was a de novo frameshift variant in SETD5, written as c.812dup; p.(Leu271PhefsTer42). One was a de novo missense variant in a gene called NEDD4L, which the authors classed as a variant of uncertain significance. One was a nonsense variant in a gene called TBL1X, inherited from his mother. The boy had intellectual disability, seizures, a brain difference called periventricular nodular heterotopia, congenital central hypothyroidism, and malformations affecting more than one organ.
The authors match each finding to a different gene rather than to SETD5 alone. They say the SETD5 variant fits his neurodevelopmental delay. They say the TBL1X variant fits his central hypothyroidism. They say the NEDD4L variant, the one they class as uncertain, is a plausible candidate for the brain difference. So this paper does not attribute the thyroid condition or that brain difference to SETD5. The authors describe this combination as, to their knowledge, the first of its kind reported, and say it shows why more than one gene is worth considering when a child's picture is complex.
This report describes one boy, so one patient out of one. He was eight years old. He had a SETD5 variant written as c.586C>T; p.Q196X. The report does not say whether this variant was de novo or inherited, and no parent testing is described. He had a history of speech delay but average intellect. He also had juvenile idiopathic arthritis, chronic recurrent multifocal osteomyelitis, ADHD, hypotonia, a narrowing of the aorta and a hole between the lower chambers of the heart. He was taking corticosteroids for the two inflammatory conditions. He was seen for headaches that had been happening for three months, on one to three days a month. They often woke him in the early morning hours. He had eye pain, strong sensitivity to light, and vomiting with some episodes. His neurological examination was normal. A brain MRI was normal. His migraine disability score was 6, which the authors describe as Grade I, little to no disability. He was given rizatriptan to take when a migraine starts. No daily preventive medicine was started.
The authors say that, to their knowledge, migraine had not been described before in this condition. They put it forward as a possible widening of the picture, not as a settled feature. They also say they cannot tell from one patient how much his SETD5 variant contributed compared with his inflammatory conditions, and they call for studies in larger groups. This is one reported patient, so the paper gives no figure for how common migraine is in SETD5 Syndrome.
This was laboratory work in mice and human cell lines. No people took part. The team asked if normal mouse development needs SETD5 to join the SET3 complex. They made mice with a SETD5 variant called W834C. It blocks this joining. They also ran gene expression testing on mouse embryonic stem cells. Those cells carried ANKRD11 or SETD5 variants that block the same joining. Mice with one copy of the W834C variant were bred together. Only five of 146 pups had two copies. The expected share is 25 percent. No results in people are reported.
The authors report that a protein called TBLR1 acts as a scaffold. It physically joins ANKRD11 and SETD5 to each other. It also links them to the rest of the NCoR complex. Both are among the proteins changed most often in brain development disorders.
This was a lab study using human astrocytes. No people or animals took part. Some cells had a SETD5 change first found in a person with autism and intellectual disability. Other cells were altered in the lab so they had less working SETD5. The team measured what the astrocytes released and tested how those substances affected healthy nerve cells.
The authors report that JAK/STAT signaling regulates the abnormal IL-6 accumulation associated with SETD5 dysfunction. Blocking JAK/STAT signaling lowered extracellular IL-6 and partially rescued astrocyte morphology and neuronal deficits in the laboratory model.
This was laboratory work and no people took part in it. The team grew human stem cells in a dish and turned them into brain cells. They made three kinds of brain cell, then switched off one risk gene per cell. They aimed at 29 genes tied to brain development, and the switch-off worked in 23. SETD5 was one of those 23. The team measured gene activity in four cell states, and SETD5 shifted activity in all four. These gene changes were built in the laboratory. They were not variants found in people with SETD5 Syndrome. A second part of the study used zebrafish, but no setd5 zebrafish. The paper reports no clinical outcome.
The authors' conclusion does not mention SETD5. They say the effects shared by these risk genes may give useful insights for the clinic. They state this as a suggestion.
Fifty-one members of one SETD5 support group on Facebook answered an online survey. They came from 12 countries. Every answer concerned SETD5-related disorder, so the SETD5 count is 51 of 51. The survey asked about medical features, challenges, and how useful the group was. Answers were self-reported, and no exam or record review is described. Of the affected people, 80% were under 18. Mean age at diagnosis was 9.2 years. There was no comparison group. The abstract does not report which SETD5 variant each person had. It also does not say who answered, parents or affected adults.
The authors say families felt stronger from sharing experience and information in the group. They say their findings widen the known range of features in this disorder. They say the findings also help with what to expect, follow-up checks, and care.
Doctors looked back at records for 192 patients at one hospital. Each had a clinical diagnosis of Noonan syndrome. Panel tests left some patients with no genetic answer. Twenty of those patients then had exome sequencing, a test that reads all the genes at once. Six of the twenty got a different diagnosis. One patient out of the 192 had a SETD5 Syndrome diagnosis. Patients joined by their Noonan diagnosis, not by a SETD5 finding. The abstract does not describe that patient or the variant.
The authors' conclusion does not mention SETD5. They say it helped to test without a set idea of the gene. A child's features were then used to pick the likely variant. They say this sorts out unclear Noonan-like cases. They also say doctors should look past RASopathies when Noonan syndrome cannot be confirmed by genes.
This is a record in a disease-naming catalogue. It is not a study. No people and no animals took part. Nothing was measured, so there is no SETD5 count to report. Orphanet gives each rare disease a number. Registries, coding systems and clinics across Europe use those numbers. Entry ORPHA:404440 was the standalone listing for a syndrome caused by SETD5 haploinsufficiency. The full entry page was read in August 2026. The page lists two papers by PubMed ID. It does not say what they support. The prevalence and inheritance fields are empty. The Orphanet gene page for SETD5 now lists no SETD5-only entry.
Orphanet has taken this entry off its list of rare diseases. It points readers to Non-specific syndromic intellectual disability instead. The record gives no reason for the removal and no date.
The study looked for new genes tied to congenital diaphragmatic hernia. In that birth defect, the muscle sheet between the chest and belly does not close. Seventeen human cases had normal results on two earlier DNA tests. All seventeen then had whole exome sequencing, a test that reads all the genes at once. Eight were tested with both parents. Nine were tested alone. At least one case out of the seventeen had a new, maybe pathogenic SETD5 variant. SETD5 was one of nine genes named as candidates. The abstract gives no count per gene. It does not name the SETD5 variant or say how it was passed on. There was no control group.
The authors' conclusion does not mention SETD5. They say no one gene or variant causes most cases of this birth defect. They also say exome sequencing worked well at finding new candidate genes and variants that add to the cause.
One person was studied: a woman of 21 with mild unusual physical features and intellectual disability. This was first blamed on a lack of oxygen at birth. A chromosome microarray found two extra pieces of DNA. One microduplication, at 3p26.3p25.2, was called pathogenic. The other, at 2q11.2, was of uncertain significance. SETD5 was one of nine genes named in the duplicated regions. The abstract does not call that list complete, or say which duplication holds SETD5. It does not say if they were de novo or inherited. This was an extra copy of SETD5, not a deletion.
The authors' conclusion does not mention SETD5. They say this case gives a long-term view of how these duplications unfold. They call for genetic testing in people with intellectual disability and mild signs. That is when birth events do not fully explain it.
Doctors at one university clinic in Wurzburg looked back at test results. The group was 400 people with a neurodevelopmental disorder and other health findings. The testing ran from 2018 to 2023. All 400 had exome sequencing. Four of the 400 had a SETD5 variant. SETD5 was one of the two genes changed most often. Sixty people also had a DNA methylation test. The methylation pattern used covers both KBG syndrome and the SETD5 disorder. It is not a SETD5-only pattern.
Some people here had a SETD5 or ANKRD11 variant that cuts the protein short. All but one of them matched the known combined episignature for both syndromes. The one who did not match had an ANKRD11 variant.
This was a look back at medical records at one center. The authors reviewed the records of 200 people with Rett syndrome. One person out of the 200 had a SETD5 finding. She was a 15-year-old girl. She had a pathogenic variant in SETD5 and one in the MECP2 gene. Her SETD5 variant was de novo. That means it was new in her, not passed down. The authors say her two findings may have happened together by chance.
The girl also had a de novo pathogenic SETD5 variant. The authors say the two changes together could mean SETD5 shaped how her illness played out. It may have added to problems early in her development. It may also have made her epilepsy more complex. They say this could be so, not that it is.
2025 publications
The authors looked at 13 people in the National Brain Gene Registry. All 13 of the 13 had a confirmed SETD5 Syndrome diagnosis. They were aged 2 to 37 years and came from 11 families. Between them they had 11 different pathogenic or likely pathogenic SETD5 variants. Six were nonsense, four were frameshift, and one was a splice site. The data came from health records, surveys and direct testing. Some people had traits not reported before, such as brain, bone and muscle problems. One person had cerebral palsy. Only the abstract could be read. It does not name the variants or say if they were de novo. It does not say which of those problems were found.
The authors say their report shows new links between SETD5 variants and health traits. They also say larger patient groups with SETD5 Disorder need study. That is needed to learn how common these health problems really are.
A team in Turkey reviewed the records of 62 children. All had autism spectrum disorder or a risk of it. Testing included whole-exome sequencing. SETD5 came up in one child out of the 62. The finding was a variant of uncertain significance. The three likely pathogenic variants were in other genes, not SETD5. The abstract gives no details on the child. It does not name the DNA change or say if it was de novo. Only the abstract was read.
The authors' conclusion does not mention SETD5. They found a gene variant in 35 percent of cases. They say this matches earlier reports. They say broad genetic testing matters when the cause of autism is unclear.
One girl with a pathogenic SETD5 variant. She was the only patient. It was found in early infancy by whole exome sequencing, a test that reads all the genes at once. The test was done for global developmental delay. The authors followed her as seizures began, using records and video-EEG. She also had a change in a second gene, GREB1L. They called it a variant of uncertain significance. They tie her urinary problems to that second variant, not to SETD5. She inherited the SETD5 variant from her mother, so it was not de novo in her. In her mother it was de novo.
The girl's mother carries the same SETD5 variant. The authors say she shared some features with her daughter, such as developmental delay and learning difficulties. She did not develop epilepsy. She did not develop major problems with thinking and learning.
This was a laboratory cell study only. The team used nerve-derived cell lines from mouse and from human. No animals and no people took part, so no person with a SETD5 finding was counted here. The team broke the ANKRD11 gene in these cells and measured what happened to SETD5. They also measured ribosomal RNA, which is part of the cell's protein-making machinery. The paper is mainly about ANKRD11 and KBG syndrome. SETD5 comes in as a gene that ANKRD11 acts upon. The authors tested that one direction only, not SETD5 acting on ANKRD11. They name the cell-line design as a limit of their work.
The authors report that ANKRD11-deficient neural cells had reduced ribosomal RNA and translation. ANKRD11 increased SETD5 expression, and overexpressing either ANKRD11 or SETD5 restored ribosomal RNA levels and translational activity.
The report covers one woman, age 25. About once a month, both her hands tingled. Her speech also failed for a few hours. A brain scan showed moyamoya angiopathy. She had no intellectual disability diagnosis. Testing used whole exome sequencing. It found a pathogenic SETD5 variant in one patient out of one. The variant leads to haploinsufficiency. The abstract calls it de novo. The main text reports no parental testing or family history.
The authors say their patient is the first such case reported. She has moyamoya angiopathy and a SETD5 variant. She has no intellectual disability.
One girl was studied in Italy. She was seen for very short height and intellectual disability. The SETD5 count is one child out of one. Exome sequencing found a de novo SETD5 variant, c.890_891delTT. The authors called it pathogenic. Her features overlapped with KBG and Cornelia de Lange syndromes. Growth hormone was started at age 12 years 6 months. Her growth rate was 3.9 cm a year before treatment, 7.2 cm in the first year and 5.8 cm in the second. Her predicted adult height rose by about 6 cm. There was no control group and no statistical test. She was still growing. Her adult height is not reported.
The authors say larger groups of patients are needed. Only then can the effect of growth hormone therapy in this condition be judged.
This report is about one fetus. That one fetus had a SETD5 variant. There was no comparison group. A heart scan before birth showed a hole low in the wall between the upper heart chambers. Doctors also suspected a hole high in the lower chamber wall. Then came whole exome sequencing, a test that reads all the genes at once. It found a new frameshift variant in SETD5. Family testing showed it was de novo. The paper also reviews past published cases. That review is behind a paywall and could not be read. The abstract does not say how far along the pregnancy was, or how it ended. No findings outside the heart are reported.
The authors looked at past published cases. They say this lets them draw together the features that mark this rare disorder.
This study was in people. Doctors sent 515 people to one lab for exome sequencing. All were born with a kidney or urinary tract problem. Two of the 515 had a SETD5 finding. Two more cases of SETD5 Syndrome came from the same lab's database. One of the two cohort variants was not reported back to the ordering doctor. It was left out of the lab's diagnosis counts. They also counted a wider group in that database. Three of fourteen people with a confirmed or likely SETD5 condition had a kidney or urinary tract problem. The range around that was wide, 4.7% to 50.8%. They compared that with a public estimate of 1 in 100. The paper does not report how common this is overall.
The authors point to their own cases. They also point to a SETD5 ranking score of 85.6% for kidney and urinary tract problems. They call this strong evidence. People with IDDD23, the SETD5 condition, can have these problems.
This was a study in people. The team ran whole genome sequencing on 195 people from 105 families. In each family, someone had Cornelia de Lange syndrome or a similar condition. 108 of the 195 people were affected. Earlier genetic testing had not found a cause. One of the 108 affected people had a SETD5 variant. It was called pathogenic or likely pathogenic. The paper does not say if this SETD5 variant was de novo. The authors note SETD5 is not usually called a Cornelia de Lange gene.
The authors say their study adds more support for one link. Features like those of Cornelia de Lange syndrome go with changes in six genes. SETD5 is one of the six. The others are ANKRD11, EP300, EHMT1, MED13L, and PHIP.
2024 publications
This was a mouse study. No people took part. Setd5 was one of three autism genes modelled. The Setd5 mice were haploinsufficient, with one working copy. Fourteen were tested against fourteen normal mice. The other models were Cul3 and Ptchd1 mice. The team tested escape from a looming shape and place avoidance. They recorded activity in a deep brain area, the dorsal periaqueductal grey. They also gave a drug that blocks a Kv1 potassium channel. No treatment in people was tested.
The authors' conclusion does not mention SETD5. They say quick seeing, run by pathways below the cortex, is tied to learning to avoid places. They say they found a source of these autism problems that is not developmental.
The paper describes 28 patients not reported before. All 28 had a SETD5 finding. Twenty-six had a single nucleotide variant and two had a copy number variation. The team looked at nerve and mind signs, EEG tests and brain MRI. Low muscle tone was in 39.2 percent. Extra or repeated movements were in 21.4 percent. Walking or fine-motor problems were in 35.7 percent. Epilepsy was in about 14 percent. Intellectual disability or global developmental delay was in 75 percent, mild to severe. Borderline intellectual functioning was in 21.4 percent. One person had a normal IQ. The abstract gives no EEG or MRI results.
The authors say these patients widen the known picture of SETD5-related disorder. They focused on nerve, mind, EEG and brain scan findings. They also reviewed past reports. They say a link between the type of change and the features may be possible.
Researchers studied 214 short patients who also had problems in more than one organ. Each had exome sequencing, a test that reads all the genes at once. Thirty-three of them had a pathogenic or likely pathogenic variant. The variants sat in nineteen genes that help control DNA. SETD5 was one of those nineteen genes, so at least one of the 214 patients had a SETD5 variant. The abstract does not say how many did. It lists webbed neck with a SETD5 variant as a feature reported for the first time. No age, sex or test details for that patient appear in the abstract.
The authors' conclusion does not mention SETD5. They say their study gives a new way to think about short stature. They also say certain clinical findings may point to a gene variant that affects how DNA is modified.
This paper describes a registry, the Brain Gene Registry. It is not a study of one condition. Thirteen research centers in the United States built it. People join if a clinical test found a variant in a brain gene. The snapshot held 479 participants and more than 200 genes. Sixteen of the 479 had a SETD5 variant. Data came from health records and from tests done at home by video. The paper reports the whole group together. It does not report results for the SETD5 participants alone. No symptoms, scores or ages are given for them.
The authors' conclusion does not mention SETD5. They say the registry is a resource for people who want to move brain gene research forward. They say it keeps signing up people whose variants were found in clinical testing. Their aim is a rich, well described national resource for research on brain development disorders.
Gaia Novarino's laboratory at IST Austria is conducting a SFARI-funded study using a conditional SETD5 knockout mouse model. This model allows researchers to selectively disable SETD5 in specific brain regions at specific developmental time points. The study is designed to identify which pathophysiological mechanisms are responsible for ASD and intellectual disability in SETD5 Syndrome, and to test whether behavioral and cognitive phenotypes can be reversed when SETD5 function is restored in adulthood. Results have not yet been published. View SFARI grant summary.
2022 publications
This was a lab study in zebrafish. No people took part. The team used CRISPR/Cas9 editing to switch off setd5 in the fish. They made one mutant fish line, with eight DNA letters deleted. Fish with one working setd5 copy were tested, a state called haploinsufficiency. So the work rests on one edited fish line and zero people. These fish grouped and swam together poorly. They also ignored other fish placed nearby. One drug, risperidone, was given, and social interest came back. Genes for synapses, the joins between nerve cells, were less active in adult fish brains. The paper reports no person with a SETD5 change.
The authors say the mutant fish show autism-like traits. They put the fish forward as a model for testing drugs, meant to reverse those behaviors.
This was a lab study in mice. No people took part. The count of people with a SETD5 change studied here is zero. The team grew mouse neural stem cells in a dish. They also studied brains of mice with one working copy of Setd5. That is called haploinsufficiency. They checked which genes were switched on. They then looked at mitochondria, the parts of a cell that make energy. They measured their shape, make-up, movement and how well they worked. The paper does not report any findings in patients.
The authors found several faults in the mitochondria. They say they can only guess where these faults sit among the causes of the disease. They say the data need confirming in patients. If confirmed, they say mitochondrial activity and movement may be new treatment targets. That would be for disorders linked to loss of SETD5.
This is a mini review. The authors ran no new experiments and no people took part. They pull together mouse studies from four separate research groups. Each group bred mice with one working copy of Setd5, a state called haploinsufficiency. The mouse lines differed, some missing more of the gene than others. They set these mouse results beside the human features of IDD23 and KBG syndrome. IDD23 is the name used here for the SETD5 condition. A KBG mouse line is covered too. The groups did not always agree on the social tests.
The authors' closing point looks ahead. They say more studies of mice with different Setd5 mutations should help. So should other mouse models of this group of conditions. Some mice could face added environmental stress, some not. The goal is to learn how the nervous system stays steady as it develops.
This was a mouse study. No people took part. The team grew pieces of mouse retina in dishes. The retina is the light-sensing layer at the back of the eye. They used a tool called shRNA to turn genes down. One of the two genes they tested was Setd5, the mouse form of SETD5. The other was Setd2. Turning Setd5 down led to an odd retinal shape. It also left fewer rod cells and fewer Müller cells. Turning Setd2 down caused none of these changes. The team then added back altered forms of the SETD5 protein. The abstract gives no counts of mice or dishes. It reports nothing about people with a SETD5 variant.
The authors say Setd5 is needed to keep retinal cells alive and dividing. They say Setd2 is not. They also say one part of the SETD5 protein, the SET domain, matters for both jobs.
This is a conference abstract, not a peer-reviewed paper. It describes two boys. Both had a pathogenic SETD5 variant, so two out of two. One boy was 15, the other was 13. Both had spine fractures and low bone mass. X-rays and bone density scans were used. Both boys had whole exome sequencing. Both were given a bone medicine called zoledronic acid. The authors report no other cause for weak bones in either boy. Neither boy had a family history of fractures. The abstract reports no results after treatment.
The authors say their two cases support a link between SETD5 and low bone mass. They add that they are looking at how SETD5 affects bone.
This is a two-page report on SETD5-related neurodevelopmental syndrome. No abstract was published. The full paper is behind a paywall. Only the title and the journal record are available. Neither one says how many people were studied. No SETD5 numerator can be given. The authors gave five keywords to the PubMed record. Keywords are index terms used for searching. They are not findings. What the authors saw cannot be checked here.
No abstract is published for this paper, so the authors' conclusion cannot be quoted here. The full paper is behind a paywall.
Doctors at The Hospital for Sick Children in Toronto wrote up a single case. One girl with a SETD5 variant is the only patient in the report. There is no comparison group. The title states that her focal epilepsy was drug-resistant. It also says her intellectual disability is linked to SETD5. No abstract was published, and the full paper was not retrievable. Her age, her brain-wave tests and her care are not stated in the title or record.
No abstract is published for this paper, so the authors' conclusion cannot be quoted here.
This is a review of past work on the SETD5 gene and protein. It reports no new data. No patients, animals or cells were studied. No person with a SETD5 finding was counted. The whole paper is about one gene, SETD5. It covers SETD5 protein structure and chromosome 3p25.3. It covers how SETD5 acts as a lysine methyltransferase on histone H3. It covers SETD5 haploinsufficiency, gene expression and thinking skills. It covers mouse work and embryo work. It also covers raised SETD5 levels in several cancers. It gives no search method and no list of studies used.
The authors say the structure and chemistry of SETD5 are now better known. They say much less is known about what SETD5 does inside cells. They also say drugs aimed at SETD5 could be one practical route in cancer.
2021 publications
Italian doctors reported one child with a SETD5 variant. That is one patient out of one, so there is no comparison group. The paper is a short letter to the journal, filed as a case report. The title says the child had novel features and a KBG syndrome-like look. No abstract was published, and the full paper is behind a paywall. So the child's features cannot be listed here. The record does not give the child's age or sex. It does not say how the variant was found. It does not say how the lab graded the variant. The database record also carries index terms. Index terms are filing labels, not findings from this paper.
No abstract is published for this paper, so the authors' conclusion cannot be quoted here. The full paper is behind a paywall.
Two doctors in China studied six children with signs of Cornelia de Lange syndrome. Each child had exome sequencing. All six had variants in genes outside the cohesin group. They then added up cases from earlier reports. That gave 46 patients across 20 non-cohesin genes. Three patients out of the 46 had SETD5 variants. Those three came from the earlier reports. Each patient was scored on the 2018 CdLS checklist. The SETD5 group averaged 7.33 points. The NIPBL group, the classic form, averaged 12.23. SETD5 enters this paper only through that review.
The authors' conclusion does not mention SETD5. They say the 11-point checklist alone can lead to a wrong CdLS diagnosis. In their view exome sequencing was needed to confirm CdLS. They say their study widens the known range of non-cohesin variants in patients with CdLS features.
The team studied 53 families. In each one, a person had obsessive-compulsive disorder, or OCD. All were adults, aged 18 to 65. People with intellectual disability or autism were not enrolled. The team read all the DNA in each family to find changes neither parent carried. These are called de novo changes. One person out of the 53 had a de novo SETD5 change. It was a missense variant, p.R77C. In lab tests this altered SETD5 lost some normal chemical activity. The paper does not describe that person's health or growth.
Four genes, including SETD5, had strong pooled evidence in this group. All four help control how genes are switched on and off. The authors say this points to one way OCD risk may arise. They mapped new DNA changes across the whole genome. They conclude that chromatin modification helps cause OCD.
2023 publications
The letter reports two patients. Both of the two had a pathogenic SETD5 variant. One was a boy of 14 and one a girl of 10. Both broke bones in the spine after minor falls. Bone tests were normal and no other cause was found. The girl's variant came from her mother. Her mother has mild to moderate intellectual disability and no bone fragility. Both children were given zoledronic acid, a bone medicine. Raw bone density rose by 7 to 14 percent. The age-adjusted Z-scores moved very little, and one moved slightly the wrong way. The paper does not say how common this is.
The authors call SETD5-related disorder a rare condition. They say the bone link is not confirmed yet. Confirming it would need clinical and imaging study of patients. They add that their paper shows a need for a low bar for bone health checks in SETD5.
Mouse study. No people took part. The team searched an online screen of mouse mutations. They sought genes whose loss caused Tbx1-like heart faults. Setd5 came up. They bred mice with one working Setd5 copy, called haploinsufficiency. Hearts were checked in 47 mouse embryos. Twelve of them had one working Setd5 copy. Two faults showed up: double outlet right ventricle and a hole between the ventricles. The team also removed both Setd5 copies from one tissue. That tissue builds part of the heart and some head and neck muscle. No human patients were studied.
In mice, Setd5 and Tbx1 did not work together. Removing both Setd5 copies from that heart-building tissue showed a new job for the gene. It was needed to lengthen the outflow tract and shape the heart chambers.
This lab study asked how the SETD5 protein controls when genes switch on. The team used mouse 3T3-L1 cells, which can turn into fat cells. They also used human kidney cells and a graft test in live mice. No people took part, so the SETD5 count is zero patients out of zero. SETD5 sat in a complex with two partner proteins, NCoR and HDAC3. The team lowered SETD5, raised it, and tracked its levels over time. The paper reports nothing about learning, behavior or any patient.
The authors say they found a new role for the timed breakdown of SETD5 protein. It helps flip gene switches called enhancers as fat cells form. They add that it is not known yet whether the same SETD5-NCoR-HDAC3 control acts this way in other growth paths.
This was a mouse study. No people took part. The SETD5 count here is zero patients out of zero. The team bred mice with Setd5 switched off only in the blood-forming system. They counted blood stem cells in these mice. They moved the cells into other mice to test long-term self-renewal. They also read which genes were switched on in those cells. Further lab work looked at how SETD5 acts with two partner proteins, HCF-1 and PAF1. The paper reports no data from people. It does not report blood problems in children with SETD5 changes.
The authors say SETD5 has an essential role in keeping adult stem cells going. It does this by controlling the pausing of RNA Polymerase II.
Doctors tested one fetus and both parents. A 13-week scan showed a septated cystic hygroma, a fluid-filled swelling. Tests on amniotic fluid found an unbalanced translocation. The fetus was missing an 11.6 Mb piece of chromosome 3. It had an extra 10.5 Mb piece of chromosome 2. The father carried the same swap in balanced form. The missing piece holds 65 genes. SETD5 is one of three there with a high haploinsufficiency score. Many genes were lost at once, not SETD5 alone.
The authors' conclusion does not mention SETD5. They say the genes hit by the translocation may have played a part. Some of the fetus's later features could come from that. They say several chromosome methods were essential in their case. The methods found the different structural changes. They also allowed fuller genetic counseling for future pregnancies.
2020 publications
Doctors report two pregnancies. In each one, a first-trimester scan showed a cystic hygroma. That is a fluid-filled swelling seen on the scan. Microarray testing of each fetus came back normal. Later scans showed no structural problems. Both pregnancies went to term with no trouble. But both children developed a neurodevelopmental syndrome before age two. Exome sequencing was then done. One child out of the two had a SETD5 variant, c.646delC. Only the abstract is available. It gives no symptom details or follow-up.
The authors' conclusion does not mention SETD5. They say doctors must stay watchful when they counsel a patient whose fetus has a first-trimester cystic hygroma. That holds even when the array result and the scans are normal. Single-gene syndromes are rare, they write, but they are possible outcomes.
Three children were studied, aged 12 to 17. All three had a clinical diagnosis of KBG syndrome. Earlier ANKRD11 testing was negative in each one. Doctors then ran array CGH and trio-based whole exome sequencing. All three of the three carried a de novo SETD5 change. One had a 116 kb deletion taking in part of SETD5. The other two had frameshift variants in SETD5. A fresh clinical review still fit KBG syndrome in some ways. Careful expert phenotyping found some face and body features that fit MRD23 better. The paper does not follow the children over time.
The authors say SETD5 loss can look like KBG syndrome. They recommend that clinicians think of 3p25 microdeletion syndrome and MRD23 when KBG syndrome is suspected, and that SETD5 be added to those gene panels.
This was a lab study in mice and in cultured cells. No people took part. The mice had one working copy of Setd5 out of two. Setd5 is the mouse form of the SETD5 gene. The team tested how these mice behaved. They also measured rDNA and ribosomal protein genes in the mouse brain. In cells, they lowered SETD5 and watched cell growth and protein making. The abstract does not give the number of mice or cells used. It reports no patient data.
The authors say SETD5 turns up rDNA activity in cells. It does this by working with a protein called HDAC3. They say this control is needed to make cyclin D1 protein. It is also needed for neural cells to grow and divide.
Before 2020
Doctors described one 11-year-old girl. She had intellectual disability, low muscle tone, and facial differences. A chromosome test called array-CGH found a deletion at 3p25.3. The missing piece was about 684 kb long. The authors lined her deletion up with three earlier case reports. All four deletions shared a 124 kb stretch. That stretch held just three named genes: THUMPD3, SETD5, and LOC440944. So SETD5 sat inside the deleted stretch in this one patient out of one. The paper does not test SETD5 or call it the cause. It reports no other patients and no follow-up.
The authors name SETD5 as one of three genes in the shared 124 kb region. They make no claim about which gene does what. They say this one girl adds to what is known about 3p deletions. They also say her case hints at links between the missing DNA and her features.
Researchers tested 996 people who had intellectual disability. One test read 565 genes at once. Seven of the 996 had a loss-of-function variant in SETD5, or 0.7 percent. Both parents were tested in only five of the seven families. So de novo status was proven in five children, not seven. Five of the seven children had behavior problems. These ranged from obsessive-compulsive disorder to hand flapping and autism features. A brain scan was done in one child, and it was normal. The other six had no brain scan. No doctor had suspected 3p25 microdeletion syndrome before the gene test.
The authors add a caution about the features they describe. With only seven children, rare features could be read as part of the condition. They say large data sets are needed to tell true links from chance findings.
Human patients. People with intellectual disability were tested for variants in the SETD5 gene. Their results were compared with people who had 3p25.3 deletions. Those deletions remove SETD5 and genes next to it. Two people had a loss-of-function variant inside SETD5. That means the gene stops working. Four more people had de novo deletions that covered SETD5. SETD5 variants made up 0.7% of the cases in this group. That is the rate here, not the rate in all people. Shared core features were intellectual disability, speech delay and behavior features. The paper does not compare outcomes between the two groups.
The authors say that variants inside SETD5 explain much of what is seen in microdeletion 3p25.3.
Eleven children took part. All had early-onset epileptic encephalopathy. All also had involuntary movements, like chorea or hand stereotypies. Nine had West syndrome. All had severe developmental delay and cognitive impairment. Ten children had exome sequencing. The eleventh had a narrower gene test. SETD5 was one of seven mutated genes found in the eleven children. The SETD5 mutation was in the West syndrome group. The abstract does not say how many carried it, or what it was. Every mutation the team found was de novo.
The authors' conclusion does not mention SETD5. They call their results preliminary, because so few children took part. They still say the features that come with seizures may matter. Extra movements or hand stereotypies are their examples. Such features could narrow the range of possible conditions. They could also help find the gene behind the illness.
The paper describes one family. Three of the three family members tested, a father and his two children, carried the SETD5 mutation. The authors used family-based exome sequencing. They also looked closely at the parents' own features. Reported features were heart defects at birth and unusual facial features. The father had only mild intellectual impairment. The abstract does not say who had which feature. It does not name the exact mutation or give the children's ages.
The authors call this the first family reported with a SETD5 mutation like this. In this family it went with heart defects at birth and unusual facial features. Two siblings and their father were affected. The effects differed between them. The authors add that testing a whole family may give a fuller picture. A close look at the parents is part of that.
This paper studies a different gene, BRPF1. It is not a SETD5 study. BRPF1 sits next to SETD5 in the 3p25 region of chromosome 3. The team used exome sequencing in one large family. Five relatives had mild intellectual disability, droopy eyelids, slow growth and low muscle tone. All five carried the same two-letter BRPF1 deletion. Six more people with BRPF1 changes were then found. None of the eleven people in this study had a SETD5 change. Cell tests looked at how the changed BRPF1 protein behaved. The authors compared symptoms in people with BRPF1 changes alone, SETD5 changes alone, or both genes deleted. The abstract does not give those group sizes.
The authors say both genes add to how severe 3p25 deletion syndrome is. But droopy eyelids and narrow eye openings come mostly from having only one working copy of BRPF1.
This was laboratory work in mice and mouse stem cells. No people took part. So no person with a SETD5 finding was counted here. The team made mice that lacked working copies of Setd5. Those embryos died between day 10.5 and 11.5 of pregnancy. They had bad defects in the neural tube, the heart, and body segments. Blood vessels formed poorly in the embryos and placentas. The team also studied stem cells with no Setd5. Those cells grew poorly and more of them died. The team checked which proteins SETD5 sticks to inside cells. They also measured histone acetylation, a chemical tag on the spools that DNA winds around.
The authors say SETD5 seems to work like two proteins in other species. One is Set3p in yeast. One is UpSET in fruit flies. They say SETD5 is needed to control histone acetylation while genes are read.
The team tested 986 people who had moderate to severe intellectual disability. They read 565 genes already linked to it or suspected of causing it. No parent DNA was used, so changes could not be confirmed as de novo. A likely cause was found in 107 of the 986 people. SETD5 was the top single gene, with seven of the 986 people. The authors say they had already reported this SETD5 finding in 2014. The paper does not describe the health or features of those seven people.
The authors' conclusion does not mention SETD5. They give their own testing advice for cases with no parent DNA. In those cases they would review every loss-of-function variant in known disability genes. They would also check a short list of missense variants already proven to cause disease.
Doctors described one boy. He was 10 years old. He had intellectual disability, feeding problems and behavior problems. He also had a leg length difference. And he had an aberrant blind ending bronchus. That is an airway branch that ends in a dead end. He joined the UK Deciphering Developmental Disorders study. He and both parents had exome sequencing. One patient, this boy, carried a de novo loss-of-function variant in SETD5. It was a frameshift in exon 12. The paper also reviews earlier published cases of SETD5 Syndrome.
The boy also had an aberrant blind ending bronchus. The authors say their report adds to reports of variants inside SETD5. They say de novo loss-of-function SETD5 variants lead to a phenotype. It overlaps 3p25 microdeletion syndromes but is still distinct.
No abstract was published for this paper. Only the title and the PubMed record are available. The title reports one patient with a de novo SETD5 nonsense mutation. That is one patient out of the one case reported. The title names two features. One is a diaphragmatic hernia, a hole in the muscle below the lungs. The other is severe cerebral cortical dysplasia. Nothing else about the patient can be read here.
No abstract is published for this paper, so the authors' conclusion cannot be quoted here. The full paper is behind a paywall.
Doctors described one man aged 36. He had mild intellectual disability with no genetic answer his whole life. One patient out of one in this report had a SETD5 variant. Exome sequencing found an insertion in the SETD5 gene. The insertion shifts the reading frame. It creates an early stop signal. Sanger testing checked the man and both parents. Neither parent carried it, so the authors called it de novo. He also had myopia and astigmatism. His brain scan and metabolic tests were normal. No other patients took part.
The authors classify this as a likely pathogenic variant. They see it as the likely genetic cause of this man's motor and thinking problems.
The authors report on seven patients whose features overlapped with Cornelia de Lange syndrome. Each one carried a mutation in a gene that helps control other genes. SETD5 was one of those genes. So at least one of the seven had a SETD5 mutation. KMT2A and genes of the SWI/SNF group were also found. A separate patient with Coffin-Siris syndrome had a missense change in NIPBL. The abstract does not say how many of the seven had SETD5. It does not list each patient's features.
The authors' conclusion does not mention SETD5. They say changes in many chromatin genes can lead to the same clinical picture. The authors add that this range of genes matters when doctors work out a diagnosis.
This was a review of cases already published. The authors also searched public disease databases. They found 42 people with variants in the SETD5 gene. The cases came from 17 papers. In 23.8% of them, the authors saw what they call autistic-like features. In all males, the SETD5 variants showed high penetrance. In females, the clinical phenotype varied more. Two female carriers had neither autism nor intellectual disability. No new patients were seen. No new genetic testing or exams were done.
The authors propose that SETD5 variants may cause a new syndrome in males. They link it to 3p25 syndrome. They say it can involve autism-related intellectual disability and differences in the shape of the face.
This was a mouse study. No people took part. In these mice, one of the two Setd5 gene copies was switched off. That state is called haploinsufficiency. The team weighed the mice and their brains. They ran learning and behavior tests. They looked at how genes were switched on in mouse tissue. Only the abstract could be read here. The number of mice is not given in it.
The authors say Setd5 helps control how genes are read and copied. It does this by working with the Hdac3 and Paf1 protein complexes. That may explain the gene activity problems seen in these mice. They say Setd5 plays a decisive role in one biological pathway. That pathway is also disrupted in people with intellectual disability and autism spectrum disorder.
Researchers studied 757 people who carried a disease-linked genetic finding. They used clinical scores, exome sequencing and microarray data. The 757 were sorted into five groups by the type of their main finding. They were not sorted by named genes. SETD5 appears once in the whole paper. One person out of the 757 carried a de novo loss-of-function variant in SETD5. That person's main finding was a 16p12.1 deletion. The paper reports no result for SETD5 as a group. The authors say they lacked the power to name individual modifier genes.
The authors' conclusion does not mention SETD5. They say a correct genetic diagnosis in complex disorders needs the whole genetic background checked. That check is needed even after one candidate disease-linked variant is found.
Two labs in the United States reviewed test results for 140,946 people with childhood-onset delay or intellectual disability. Twelve had a SETD5 change, called pathogenic or likely pathogenic. The paper adds 14 new patients and reviews 14 reported before. Testing used exome sequencing of the child and both parents. Most changes were de novo. One patient inherited it from an unaffected mother; twin boys inherited theirs from a mildly affected mother.
In some women who carried a SETD5 change, the signs were mild or absent. The authors say that has impacts on genetic counseling and family planning.
This is a case report about one child. The report is short and has no abstract. The title says the child had a de novo deletion. About 10.1 megabases were missing from the end of chromosome 3p25. SETD5 sat inside that missing piece, one patient out of one. The title also lists ptosis, a drooping eyelid, and psychomotor retardation. A deletion this large removes many other genes too. So it is not clear which features come from SETD5 alone. The full text could not be read here. Age, sex, test methods and family details are not reported.
No abstract is published for this paper, so the authors' conclusion cannot be quoted here.
This was a mouse and cell study. No people took part, so zero patients out of zero had a SETD5 finding. The team studied the retina of newborn mice and lab-grown cells. They followed a small molecule, miR-126-5p, and the mouse SetD5 gene. In the retina, miR-126-5p turned SetD5 down, which kept a protein called Sema3A low. That helped young blood vessel cells survive. When SetD5 went up, Sema3A went up and those cells died. This was normal eye development, not eye disease. The paper does not study people or SETD5 haploinsufficiency.
In mice, miR-126-5p held SetD5 down in retinal nerve cells. That kept Sema3A low. The authors call SetD5 an uncharacterized member of the methyltransferase family. They conclude that miR-126-5p, made in nerve cells, shapes blood vessel growth by keeping the retina's blood vessel cells from dying.
This was a mouse study. No people took part. The mice carried one working copy of the Setd5 gene. Researchers call this haploinsufficiency. Mice with no working copy died before birth. Behavior tests used ten mice of each sex, for each genotype. Brain scans covered eleven Setd5 mice and twelve normal mice. The team also grew mouse brain cells in a dish. They looked at cell growth, synapses and network activity. They also read gene activity in the developing cortex. No treatment was tested.
The authors say the brain scan differences cannot yet be called the cause of the behavior changes. The same mice were not used for both tests. They say their mouse model points to Setd5 loss harming early brain development. Faulty gene activity in some brain cells may weaken wiring and change behavior.
This was lab work, not a study of people. SETD5 is the single gene at the heart of it. The team used mice, zebrafish and neural stem cells. Mice were bred with one broken copy of Setd5. That state is called haploinsufficiency. The authors checked how brain stem cells divide. They checked how neurons wire up to each other. They also measured a chemical tag on gene bodies. Mouse behavior was tested as well. The abstract gives no animal or cell counts. Only the abstract is available.
The authors say SETD5 acts as an enzyme that controls which genes get read. That control matters in brain stem cells and the cells they become. They say their work shows the steps that link these faults to problems in neurons. Those neuron problems sit behind related human diseases.
This report covers one child. One patient out of one had a SETD5 variant. She was a girl of 1.7 years with severe intellectual disability. Her motor skills were delayed. She had language problems and unusual facial features. Her genes were read by exome sequencing. The authors found a SETD5 frameshift variant not seen before. A frameshift stops the protein early. Both parents tested negative for it. So the authors call it de novo. Her brain scan showed white matter changes and wider fluid spaces. No treatment is reported.
The authors found a new SETD5 variant in this one child. They call it the likely genetic cause of her intellectual disability. They say the finding may help deepen understanding of this condition.
Human study. The team studied 39 children who had moyamoya angiopathy, a condition where arteries in the brain slowly narrow. Their parents were tested too. The team used exome sequencing. They looked for a de novo variant. One child out of the 39 had a de novo SETD5 frameshift variant. A separate group of 158 unrelated people with the condition was also checked. Two of them had rare SETD5 missense variants. That is a different kind of change. The authors say SETD5 tolerates missense variants. People joined because of the brain condition, not because of a SETD5 variant. The paper does not show that SETD5 variants cause it.
The authors say more data are needed before this link can be treated as proven. They also say they cannot yet recommend brain scans for people who carry these variants. More would need to be known first about how often moyamoya happens in them.
Researchers looked at 57 families. In each one, a child was thought to have Cornelia de Lange syndrome, or CdLS. The team ran exome sequencing, a test that reads all the protein-coding genes. They found a pathogenic change in 36 of the 57 families. Two known CdLS genes explained 25 of those. Four other genes each explained one patient. SETD5 was one of the four, so one patient out of 57. The abstract does not describe that patient's SETD5 variant. It does not list their symptoms.
The authors' conclusion does not mention SETD5. They scored all the patients with a new CdLS scoring system. From that, they say changes in ZMYND11, MED13L and PHIP may cause CdLS. Or they may cause a CdLS-like condition.