Clinical characteristics.

SETD1B-related neurodevelopmental disorder (SETD1B-NDD) is characterized by developmental delay (mainly affecting speech and language), intellectual disability, seizures, autism spectrum disorder or autism-like behaviors, and additional behavioral concerns. Speech delay and/or language disorder has been reported in most affected individuals. Delay in gross motor skills and mild-to-moderate intellectual disability are common. Most affected individuals have seizures with variable onset and seizure type. Behavioral issues including hyperactivity, aggression, anxiety, and sleep disorders have been reported in approximately half of individuals. Less common features include ophthalmologic manifestations and feeding issues.

Diagnosis/testing.

The diagnosis of SETD1B-NDD is established in a proband with developmental delay / intellectual disability and a heterozygous pathogenic variant in SETD1B identified by molecular genetic testing.

Management.

Treatment of manifestations: Developmental support services and educational intervention; standard treatment with anti-seizure medication in those with seizures; early intervention as needed for feeding problems; standard orthopedic management and therapies for spasticity; routine management of ophthalmologic issues and hearing impairment; social work support and care coordination.

Surveillance: At each visit, assessment of growth, feeding, developmental progress, changes in seizures, behavioral issues, sleep issues, musculoskeletal issues, mobility, and need for social work support and care coordination.

Genetic counseling.

SETD1B-NDD is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Most individuals diagnosed with SETD1B-NDD have the disorder as the result of a de novo pathogenic variant. Vertical transmission of a SETD1B pathogenic variant from an affected mother to an affected child has been reported in one family. Each child of an individual with SETD1B-NDD has a 50% chance of inheriting the pathogenic variant. Once the SETD1B pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

SETD1B-related neurodevelopmental disorder (SETD1B-NDD) should be considered in individuals with the following clinical findings:

• Developmental delay (especially speech and language delay)
• Intellectual disability (ID)
• Seizures that are frequently refractory to treatment
• Autism spectrum disorder or autism-like behaviors
• Other behavioral concerns (hyperactivity, aggression, anxiety, sleep disorders)

Establishing the Diagnosis

The diagnosis of SETD1B-NDD is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in SETD1B identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous SETD1B variant of uncertain significance does not establish or rule out a diagnosis.

Because the phenotype of SETD1B-NDD is indistinguishable from many other inherited disorders with ID and/or seizures, molecular genetic testing approaches can include use of comprehensive genomic testing (exome sequencing, genome sequencing) or a multigene panel.

Note: Single-gene testing (e.g., sequence analysis of SETD1B) is rarely useful and typically NOT recommended.

• Comprehensive genomic testing may be considered. Exome sequencing is most commonly used. To date, the majority of SETD1B pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing. Genome sequencing is also possible to detect variants outside the coding region.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
• An ID or epilepsy multigene panel that includes SETD1B and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Resolution of variants of uncertain significance (VUS). Many disorders that perturb regulators of epigenetic processes result in a very specific DNA methylation pattern that is common to all affected individuals with pathogenic variants in that gene [Aref-Eshghi et al 2020]. Identification of an episignature characteristic of SETD1B-NDD can be used to resolve VUS in SETD1B [Krzyzewska et al 2019] (see Molecular Genetics). Laboratory geneticists should note that there may be more than one episignature associated with SETD1B-NDD, since loss-of-function and partial loss-of-function variants may produce episignatures that are different and distinguishable from episignatures produced by gain-of-function variants and variants with other modes of action.

Clinical Description

SETD1B-related neurodevelopmental disorder (SETD1B-NDD) is characterized by developmental delay (mainly affecting speech and language), intellectual disability, seizures, autism spectrum disorder or autism-like behaviors, and additional behavioral concerns including sleep disturbances. To date, 38 individuals have been identified with a pathogenic variant in SETD1B [Roston et al 2021, Weerts et al 2021, Álvarez-Mora et al 2022, Weng et al 2022]. The following description of the phenotypic features associated with SETD1B-NDD is based on these reports.

Global developmental delay. Speech delay and/or language disorders have been reported in most affected individuals. The range of speech impairment varied from isolated delays to more severe impairments. Of individuals for whom age at first word was reported, 14 of 30 spoke their first word after age two years [Roston et al 2021, Weerts et al 2021]. Out of a cohort of 36 individuals with SETD1B-NDD, three individuals were nonverbal at ages 2.5, 3, and 3.5 years [Weerts et al 2021]. Only two individuals were reported not to have language delay, and they were very young (10 and 12 months) at the time of assessment [Weerts et al 2021].

Delay in gross motor skills is frequent. When reported specifically, age at first walking ranged from 12 months to 4.5 years. One individual was reported as having normal motor development at age seven years [Hiraide et al 2019]. Detailed reports of fine motor milestones in individuals with SETD1B-NDD have yet to be published.

Developmental regression was observed in six of 38 individuals with SETD1B-NDD, and regression did not always coincide with seizure onset. Regression primarily affected speech; detailed descriptions of motor regression have not been published [Roston et al 2021, Weerts et al 2021, Álvarez-Mora et al 2022, Weng et al 2022].

The two individuals with reported normal development were evaluated at ages one and two years, and additional information for these individuals is not available.

Intellectual disability (ID) appears to be typically mild to moderate: 13 individuals with mild ID and ten individuals with moderate ID were reported. One individual was reported to have severe ID [Weerts et al 2021] and another individual was reported to have profound ID [Hiraide et al 2018].

Note: Patients reported as “intellectually disabled” at age younger than three years are included in global developmental delay.

Seizures. Affected individuals typically presented with seizures by age five years, although seizure onset at older ages was reported in six individuals [Roston et al 2021, Weerts et al 2021]. Two individuals with SETD1B-NDD presented with seizures at age six months or younger [Weerts et al 2021].

Seizure types were heterogeneous, and often included multiple seizure types or evolving seizure patterns. Seizure types included absence (18 individuals), myoclonic (13 individuals), generalized tonic-clonic (12 individuals), focal (4 individuals), and atonic (2 individuals). Of note, at least four individuals demonstrated eyelid myoclonia [Roston et al 2021, Weerts et al 2021].

Seizures occurred daily in most individuals and were reported to worsen with age. Seizures were intractable in at least four individuals [Roston et al 2021, Weerts et al 2021]. However, some individuals reported improvement with anti-seizure medication. No consistently effective anti-seizure treatment was identified.

Feeding difficulties have been reported in a small proportion of individuals.

Other neurologic findings

• Hypotonia in infancy or early childhood was reported in 15 of 34 individuals [Roston et al 2021, Weerts et al 2021, Weng et al 2022].
• Microcephaly, with a head circumference of 2 SD below the mean, was identified in one adult with SETD1B-NDD [Weerts et al 2021].

Autism spectrum disorder and autistic features. The majority of reported individuals were either diagnosed with autism spectrum disorder (22/37) or had autistic features without a formal diagnosis (4 */37) [Roston et al 2021, Weerts et al 2021, Weng et al 2022].

* Includes patients reported as “autistic” at age younger than three years

Other behavioral concerns. Approximately half of reported individuals had other behavioral concerns including hyperactivity (10 individuals), aggression (9), anxiety (6), and sleep disturbance (6). A further three individuals demonstrated obsessive-compulsive behavior [Roston et al 2021, Weerts et al 2021, Weng et al 2022]. Behavioral issues have been more common in affected males.

Brain MRI abnormalities included nonspecific white matter hyperintensities, abnormalities of the corpus callosum, cystic encephalomalacia with ventriculomegaly, bilateral abnormal signals in multiple lobes, extensive abnormal gyral sulcation, delayed myelination and heterotopic grey matter, and periventricular leukomalacia. Of note, several individuals with abnormal brain MRI findings had an additional serious medical condition (e.g., periventricular leukomalacia in an individual with hypoplastic left heart) [Roston et al 2021, Weerts et al 2021, Weng et al 2022].

Nonspecific facial features. Many individuals with SETD1B-NDD were reported to have unusual craniofacial features, but without a clear recognizable pattern. Ear anomalies were common (e.g., overfolded helices, differences of ear lobe morphology, ear pits, ear tags). Several individuals had a high anterior hairline, frontal bossing, or anterior hairline recession [Roston et al 2021, Weerts et al 2021, Weng et al 2022]. Thickened facial features (e.g., full cheeks, thick lips, broad or bulbous nasal tip, wide nasal root) were frequently reported; it is unknown if coarse facial features were secondary to anti-convulsant therapy.

Ophthalmologic features. Strabismus has been reported infrequently; astigmatism, amblyopia, and myopia have also been reported [Weerts et al 2021].

Other. Each reported in one individual:

• Dysplastic kidneys requiring transplant, an anteriorly placed anus, clubfeet, tethered cord, and contractures [Weerts et al 2021]
• Cryptorchidism requiring surgery [Weerts et al 2021]
• Hearing impairment [Weerts et al 2021]
• Hypoplastic left heart [Weerts et al 2021]
• Patent ductus arteriosus [Roston et al 2021]

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Penetrance

The penetrance of SETD1B-NDD is predicted to be high. To date, no individuals have been confirmed to have inherited a pathogenic variant from an unaffected parent, and one individual inherited a pathogenic variant from an affected parent [Roston et al 2021, Weerts et al 2021].

Prevalence

SETD1B-NDD is rare, with only 38 individuals with a pathogenic (or likely pathogenic) SETD1B variant reported to date. Males appear to be disproportionately represented in the literature; 24 of 38 reported individuals are male (male-to-female ratio: ~1.7:1) [Roston et al 2021, Weerts et al 2021, Álvarez-Mora et al 2022, Weng et al 2022].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SETD1B-NDD, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

In general, women with epilepsy or a seizure disorder of any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication (ASM) during pregnancy reduces this risk. However, exposure to ASM may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASM to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [Sarma et al 2016].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

SETD1B-related neurodevelopmental disorder (SETD1B-NDD) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with SETD1B-NDD have the disorder as the result of a de novo SETD1B pathogenic variant.
• Vertical transmission of a SETD1B pathogenic variant from an affected mother to an affected child has been reported in one family [Weerts et al 2021].
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
    * A parent with somatic and germline mosaicism for an SETD1B pathogenic variant may be mildly/minimally affected.
• The family history of some individuals diagnosed with SETD1B-NDD may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the SETD1B pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the SETD1B pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the SETD1B pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for SETD1B-NDD because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with SETD1B-NDD has a 50% chance of inheriting the SETD1B pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the SETD1B pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

Prenatal Testing and Preimplantation Genetic Testing

Once the SETD1B pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Histone methyltransferases (HMTs) are a group of proteins that modify chromatin, thus regulating gene expression, through the addition of methyl groups to histones. A specific class of HMTs is the H3K4 family (histone-3-methyl-4), which methylate the fourth lysine residue on the tail of histone 3. This epigenetic modification allows for the packaging of DNA into heterochromatin. SETD1B encodes the protein SET domain-containing protein 1B (SETD1B), a lysine-specific methyltransferase involved in histone methylation [Yang & Ernst 2017]. In combination with four additional subunits, SETD1B forms the catalytic component of one of these HMT enzymes and assists in epigenetic regulation of gene expression [Nagase et al 1999, Lee et al 2007]. Therefore, SETD1B is believed to be an epigenetic modifier of chromatin structure, affecting expression of multiple downstream genes [Nagase et al 1999].

Studies have shown a strong effect of SETD1B function on DNA methylation. Specifically, it has been suggested that loss of SETD1B function may lead to the insufficient production of H3K4me3 and DNA hypermethylation in specific loci. This specific epigenetic methylation signature associated with SETD1B loss-of-function variants was used to reclassify two SETD1B variants of uncertain significance as pathogenic [Krzyzewska et al 2019].

Mechanism of disease causation. It is believed that SETD1B-related neurodevelopmental disorder (SETD1B-NDD) is most likely caused by loss-of-function or partial loss-of-function SETD1B variants; however, further functional studies are required to confirm this mechanism [Roston et al 2021, Weerts et al 2021].

Cancer and Benign Tumors

Somatic variants affecting H3K4 methyltransferases, including SETD1B, have been identified in various tumors. Functional studies have suggested a role for both gain-of-function and loss-of-function variants in hematologic malignancies [Schmidt et al 2014, Yang & Ernst 2017]. Somatic SETD1B variants have been identified in endometrial cancer and may have a role in predicting the degree of myometrial invasion [García-Sanz et al 2017]. To date, malignancy has been described in only one individual with SETD1B-NDD; a well-differentiated tubular adenocarcinoma of the sigmoid colon was diagnosed in an individual at age 30 years [Hiraide et al 2018]. No affected individuals have to date been reported to develop malignancies in childhood [Roston et al 2021, Weerts et al 2021, Álvarez-Mora et al 2022, Weng et al 2022].

Author Notes

William T Gibson, MD, PhD (Cantab), FRCPC, FCCMG, is a Senior Clinician-Scientist at the British Columbia Children's Hospital Research Institute in Vancouver, Canada. His research focuses on rare epigenetic disorders, particularly those that cause neurodevelopmental effects and/or overgrowth. His researcher profile is viewable at bcchr.ca/wgibson and his team may be contacted at ac.rhccb@yrtsigercitenegipe.

Alexandra Roston, MD, is an FRCPC Clinician Investigator trainee with British Columbia's Provincial Medical Genetics Program in Vancouver. She may be contacted professionally at ac.ashp@notsor.ardnaxela.

Acknowledgments

The authors would like to thank the many individuals with SETD1B-related neurodevelopmental disorder who generously gave their permission to be included in this research.

Revision History

• 29 September 2022 (sw) Review posted live
• 10 June 2022 (wg) Original submission

Literature Cited

• Álvarez-Mora MI, Sánchez A, Rodríguez-Revenga L, Corominas J, Rabionet R, Puig S, Madrigal I. Diagnostic yield of next-generation sequencing in 87 families with neurodevelopmental disorders. Orphanet J Rare Dis. 2022;17:60. [PMC free article: PMC8858550] [PubMed: 35183220]
• Aref-Eshghi E, Kerkhof J, Pedro VP, Groupe DI. France, Barat-Houari M, Ruiz-Pallares N, Andrau JC, Lacombe D, Van-Gils J, Fergelot P, Dubourg C, Cormier-Daire V, Rondeau S, Lecoquierre F, Saugier-Veber P, Nicolas G, Lesca G, Chatron N, Sanlaville D, Vitobello A, Faivre L, Thauvin-Robinet C, Laumonnier F, Raynaud M, Alders M, Mannens M, Henneman P, Hennekam RC, Velasco G, Francastel C, Ulveling D, Ciolfi A, Pizzi S, Tartaglia M, Heide S, Héron D, Mignot C, Keren B, Whalen S, Afenjar A, Bienvenu T, Campeau PM, Rousseau J, Levy MA, Brick L, Kozenko M, Balci TB, Siu VM, Stuart A, Kadour M, Masters J, Takano K, Kleefstra T, de Leeuw N, Field M, Shaw M, Gecz J, Ainsworth PJ, Lin H, Rodenhiser DI, Friez MJ, Tedder M, Lee JA, DuPont BR, Stevenson RE, Skinner SA, Schwartz CE, Genevieve D, Sadikovic B. Evaluation of DNA methylation episignatures for diagnosis and phenotype correlations in 42 Mendelian neurodevelopmental disorders. Am J Hum Genet. 2020;106:356–70. [PMC free article: PMC7058829] [PubMed: 32109418]
• Baple E, Palmer R, Hennekam RC. A microdeletion at 12q24.31 can mimic Beckwith-Wiedemann syndrome neonatally. Mol Syndromol. 2010;1:42–5. [PMC free article: PMC2883851] [PubMed: 20648245]
• Chouery E, Choucair N, Abou Ghoch J, El Sabbagh S, Corbani S, Mégarbané A. Report on a patient with a 12q24.31 microdeletion inherited from an insulin-dependent diabetes mellitus father. Mol Syndromol. 2013;4:136–42. [PMC free article: PMC3638924] [PubMed: 23653585]
• Den K, Kato M, Yamaguchi T, Miyatake S, Takata A, Mizuguchi T, Miyake N, Mitsuhashi S, Matsumoto N. A novel de novo frameshift variant in SETD1B causes epilepsy. J Hum Genet. 2019;64:821–7. [PubMed: 31110234]
• García-Sanz P, Triviño JC, Mota A, Pérez López M, Colás E, Rojo-Sebastián A, García Á, Gatius S, Ruiz M, Prat J, López-López R, Abal M, Gil-Moreno A, Reventós J, Matias-Guiu X, Moreno-Bueno G. Chromatin remodelling and DNA repair genes are frequently mutated in endometrioid endometrial carcinoma. Int J Cancer. 2017;140:1551–63. [PubMed: 27997699]
• Hiraide T, Hattori A, Ieda D, Hori I, Saitoh S, Nakashima M, Saitsu H. De novo variants in SETD1B cause intellectual disability, autism spectrum disorder, and epilepsy with myoclonic absences. Epilepsia Open. 2019;4:476–81. [PMC free article: PMC6698685] [PubMed: 31440728]
• Hiraide T, Nakashima M, Yamoto K, Fukuda T, Kato M, Ikeda H, Sugie Y, Aoto K, Kaname T, Nakabayashi K, Ogata T, Matsumoto N, Saitsu H. De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism. Hum Genet. 2018;137:95–104. [PubMed: 29322246]
• Krzyzewska IM, Maas SM, Henneman P, Lip KVD, Venema A, Baranano K, Chassevent A, Aref-Eshghi E, van Essen AJ, Fukuda T, Ikeda H, Jacquemont M, Kim HG, Labalme A, Lewis SME, Lesca G, Madrigal I, Mahida S, Matsumoto N, Rabionet R, Rajcan-Separovic E, Qiao Y, Sadikovic B, Saitsu H, Sweetser DA, Alders M, Mannens MMAM. A genome-wide DNA methylation signature for SETD1B-related syndrome. Clin Epigenetics. 2019;11:156. [PMC free article: PMC6830011] [PubMed: 31685013]
• Labonne JD, Lee KH, Iwase S, Kong IK, Diamond MP, Layman LC, et al. An atypical 12q24.31 microdeletion implicates six genes including a histone demethylase KDM2B and a histone methyltransferase SETD1B in syndromic intellectual disability. Hum Genet. 2016;135:757–71. [PubMed: 27106595]
• Lee JH, Tate CM, You JS, Skalnik DG. Identification and characterization of the human Set1B histone H3-Lys4 methyltransferase complex. J Biol Chem. 2007;282:13419–28. [PubMed: 17355966]
• Nagase T, Ishikawa K, Suyama M, Kikuno R, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O. Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 1999;6:63–70. [PubMed: 10231032]
• Palumbo O, Palumbo P, Delvecchio M, Palladino T, Stallone R, Crisetti M, Zelante L, Carella M. Microdeletion of 12q24.31: report of a girl with intellectual disability, stereotypies, seizures and facial dysmorphisms. Am J Med Genet Part A. 2015;167A:438–44. [PubMed: 25428890]
• Qiao Y, Tyson C, Hrynchak M, Lopez-Rangel E, Hildebrand J, Martell S, Fawcett C, Kasmara L, Calli K, Harvard C, Liu X, Holden JJ, Lewis SM, Rajcan-Separovic E. Clinical application of 2.7M Cytogenetics array for CNV detection in subjects with idiopathic autism and/or intellectual disability. Clin Genet. 2013;83:145–54. [PubMed: 22369279]
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Roston A, Evans D, Gill H, McKinnon M, Isidor B, Cogné B, Mwenifumbo J, van Karnebeek C, An J, Jones SJM, Farrer M, Demos M, Connolly M, Gibson WT, et al. SETD1B-associated neurodevelopmental disorder. J Med Genet. 2021;58:196–204. [PubMed: 32546566]
• Sarma AK, Khandker N, Kurczewski L, Brophy GM. Medical management of epileptic seizures: challenges and solutions. Neuropsychiatr Dis Treat. 2016;12:467–85. [PMC free article: PMC4771397] [PubMed: 26966367]
• Schmidt K, Kranz A, Stewart F, Anastassiadis K. Functional examination of the H3K4 histone methyltransferases setd1b and Mii2 in myeloid neoplasia. Exp Hematol. 2014;42:S58.
• Weerts MJA, Lanko K, Guzmán-Vega FJ, Jackson A, Ramakrishnan R, Cardona-Londoño KJ, Peña-Guerra KA, van Bever Y, van Paassen BW, Kievit A, van Slegtenhorst M, Allen NM, Kehoe CM, Robinson HK, Pang L, Banu SH, Zaman M, Efthymiou S, Houlden H, Järvelä I, Lauronen L, Määttä T, Schrauwen I, Leal SM, Ruivenkamp CAL, Barge-Schaapveld DQCM, Peeters-Scholte CMPCD, Galehdari H, Mazaheri N, Sisodiya SM, Harrison V, Sun A, Thies J, Pedroza LA, Lara-Taranchenko Y, Chinn IK, Lupski JR, Garza-Flores A, McGlothlin J, Yang L, Huang S, Wang X, Jewett T, Rosso G, Lin X, Mohammed S, Merritt JL 2nd, Mirzaa GM, Timms AE, Scheck J, Elting MW, Polstra AM, Schenck L, Ruzhnikov MRZ, Vetro A, Montomoli M, Guerrini R, Koboldt DC, Mosher TM, Pastore MT, McBride KL, Peng J, Pan Z, Willemsen M, Koning S, Turnpenny PD, de Vries BBA, Gilissen C, Pfundt R, Lees M, Braddock SR, Klemp KC, Vansenne F, van Gijn ME, Quindipan C, Deardorff MA, Hamm JA, Putnam AM, Baud R, Walsh L, Lynch SA, Baptista J, Person RE, Monaghan KG, Crunk A, Keller-Ramey J, Reich A, Elloumi HZ, Alders M, Kerkhof J, McConkey H, Haghshenas S, Maroofian R, Sadikovic B, Banka S, Arold ST, Barakat TS, et al. Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome. Genet Med. 2021;23:2122–37. [PMC free article: PMC8553606] [PubMed: 34345025]
• Weng R, Nenning KH, Schwarz M, Riedhammer KM, Brunet T, Wagner M, Kasprian G, Lehrner J, Zimprich F, Bonelli SB, Krenn M. Connectome analysis in an individual with SETD1B-related neurodevelopmental disorder and epilepsy. J Dev Behav Pediatr. 2022;43:e419–e422. [PubMed: 35385430]
• Yang W, Ernst P. Distinct functions of histone H3, lysine 4 methyltransferases in normal and malignant hematopoiesis. Curr Opin Hematol. 2017;24:322–8. [PMC free article: PMC5603181] [PubMed: 28375985]