Clinical characteristics.

Wiedemann-Steiner syndrome (WSS) is characterized by developmental delay, intellectual disability, and characteristic facial features, with or without additional congenital anomalies. The facial features include thick eyebrows with lateral flare, vertically narrow and downslanted palpebral fissures, widely spaced eyes, long eyelashes, wide nasal bridge, broad nasal tip, thin vermilion of the upper lip, and thick scalp hair. About 60% of affected individuals have hypertrichosis cubiti ("hairy elbows"), which was once thought to be pathognomic for the syndrome, with a majority having hypertrichosis of other body parts. Other clinical features include feeding difficulties, prenatal and postnatal growth restriction, epilepsy, ophthalmologic anomalies, congenital heart defects, hand anomalies (such as brachydactyly and clinodactyly), hypotonia, vertebral anomalies (especially fusion anomalies of the cervical spine), renal and uterine anomalies, immune dysfunction, brain malformations, and dental anomalies.

Diagnosis/testing.

The diagnosis of WSS is established in a proband with suggestive findings and a heterozygous pathogenic variant in KMT2A identified by molecular genetic testing.

Management.

Treatment of manifestations: Feeding therapy with possible supplemental tube feeding for those with poor weight gain / failure to thrive; growth hormone therapy for those with growth hormone deficiency; thyroid replacement therapy for hypothyroidism; consideration of IVIG therapy in those with low antibody levels; consideration of prophylactic antibiotics in those with frequent infections; stool softeners or osmotic agents for bowel dysfunction; oculoplasty for blepharoptosis; CPAP, BiPAP, or surgical removal of the tonsils and adenoids for those with obstructive sleep apnea; behavioral therapy; standard treatment for epilepsy, developmental delay / intellectual disability, congenital hip dysplasia, cervical vertebral fusion, eye anomalies, congenital heart defects, renal anomalies, uterine anomalies, and metabolic bone disease (which may include vitamin D supplementation).

Surveillance: At each visit: measurement of growth parameters; evaluation of nutritional status; assessment for constipation; evaluation for new neurologic features and seizure activity with EEG follow up as indicated; assessment of clinical signs of medullar compression; monitoring for signs/symptoms of arrhythmia; assessment of developmental progress, behavior, and physical skills; monitoring for frequent infections. Dental evaluation every six months after the eruption of primary teeth. Assessment for premature thelarche or primary amenorrhea in childhood until growth/menarche is complete. Ophthalmologic evaluation annually, or as clinically indicated.

Agents/circumstances to avoid: The authors are aware of one individual with WSS who developed hyperammonemia with the use of the anti-seizure medication valproate. While this is not specific to individuals with WSS, valproate should be used with caution.

Pregnancy management: In affected pregnant women who have a seizure disorder, discussion of the most appropriate anti-seizure medication regimen during pregnancy is recommended. Cervical spine anomalies may lead to immobility or instability, which may complicate airway management. Vertebral anomalies or scoliosis in the thoracic or lumbar spine may complicate spinal or epidural anesthesia.

Genetic counseling.

Most individuals diagnosed with WSS whose parents have undergone molecular genetic testing have the disorder as the result of a de novo pathogenic variant. Rarely, individuals diagnosed with WSS have an affected parent. In this situation, WSS can be inherited in an autosomal dominant fashion. Each offspring of an individual with WSS is at a 50% risk of being affected. Once the KMT2A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

Wiedemann-Steiner syndrome should be suspected in individuals with the following clinical, imaging, and family history findings.

Clinical findings

• Distinctive facial features (Figures 1, 2, 3)
• Hypertrichosis cubiti ("hairy elbows"), hypertrichosis of the back, and/or hypertrichosis of the lower limbs
• Sacral dimple
• Developmental delay / intellectual disability
• Hypotonia
• Feeding difficulties
• Failure to thrive
• Short stature
• Constipation

Figure 1.

Individuals with characteristic facial features of Wiedemann-Steiner syndrome; first 15 are shown in front and side views. Modified from Sheppard et al [2021]

Figure 2.

Individuals with characteristic facial features of Wiedemann-Steiner syndrome: family groups A. 3 sibs shown in front and side views

Figure 3.

Eight individuals with Wiedemann-Steiner syndrome shown as they age Modified from Sheppard et al [2021]

Imaging findings

• Abnormal brain MRI, most commonly demonstrating abnormalities of the corpus callosum or abnormal myelination
• Congenital heart disease
• Genitourinary anomalies, most commonly vesiculouretal reflux with hydronephrosis, cryptorchidism in males, or absent uterus in females
• Vertebral anomalies, especially fusion anomalies in the cervical spine

Family history. Because WSS is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations).

Establishing the Diagnosis

The diagnosis of WSS is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in KMT2A 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 KMT2A variant of uncertain significance does not establish or rule out a diagnosis. (3) Because KMT2A is a histone methyltransferase that regulates chromatin-mediated transcription (see Molecular Genetics), it has the ability to alter the epigenetic state of the genome; as such, assessment of the epigenetic signature may be considered to aid in the interpretation of the pathogenicity of a variant of uncertain clinical significance.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype. Methylation studies, such as an epigenetic signature, can be considered in those individuals who have suggestive findings but in whom no pathogenic variant in KMT2A has been identified via sequence analysis or genomic testing.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with intellectual disability are more likely to be diagnosed using comprehensive genomic testing (see Option 2).

Clinical Description

Wiedemann-Steiner syndrome (WSS) is characterized by developmental delay, intellectual disability, and characteristic facial features, with or without additional congenital anomalies. To date, more than 200 individuals have been reported in the medical literature with a pathogenic variant in KMT2A [Jones et al 2012, Mendelsohn et al 2014, Strom et al 2014, Bramswig et al 2015, Calvel et al 2015, Steel et al 2015, Yuan et al 2015, Miyake et al 2016, Stellacci et al 2016, Aggarwal et al 2017, Bogaert et al 2017, Enokizono et al 2017, Min Ko et al 2017, Sun et al 2017, Baer et al 2018, Lebrun et al 2018, Li et al 2018, Stoyle et al 2018, Chan et al 2019, Chen et al 2019, Feldman et al 2019, Negri et al 2019, Giangiobbe et al 2020, Matis et al 2020, Mendoza 2020, Demir et al 2021, Di Fede et al 2021, Nardello et al 2021, Sheppard et al 2021]. The following description of the phenotypic features associated with this condition is based on these reports.

Characteristic dysmorphic features. Hypertrichosis cubiti, initially thought to be pathognomonic, is present in the majority of affected individuals [Strom et al 2014, Aggarwal et al 2017, Baer et al 2018, Sheppard et al 2021]. Characteristic facial features:

• Thick eyebrows
• Long eyelashes
• Vertically narrow palpebral fissures
• Widely spaced eyes
• Wide nasal bridge with broad or bulbous tip
• Lateral (or other) flare to the eyebrow
• Downslanted palpebral fissures
• Blepharoptosis
• Exaggerated Cupid's bow
• Thin vermilion border to the upper lip
• Posteriorly rotated ears

Developmental delay. Most affected individuals have delayed developmental milestones, and some remain nonverbal and nonambulatory [Baer et al 2018, Li et al 2018, Chan et al 2019, Sheppard et al 2021]. The median ages for developmental milestones:

• Sitting. Ten months (range 6-36 months)
• Standing. 17 months (range 8-60 months)
• Walking. 20 months (range 11-60 months)
• First words. 18 months (range 8-60 months)

Intellectual disability and educational achievement. Most affected individuals require some degree of special education, but the majority of adults in one study completed high school.

• Some affected individuals are able to maintain jobs as adults.
• IQ in those tested ranges from 40 to 85 (median 65).
• For more detailed information on developmental and learning issues, see Feldman et al [2019] and Sheppard et al [2021].

Behavioral problems. About 30% of affected individuals have aggressive behavior such as self-harm, though some also have physical aggression and tantrums. About 20% of affected individuals have autistic features suggestive of an autism spectrum diagnosis. Many children with WSS are described by their families as sweet and having a happy demeanor [Sheppard et al 2021].

Growth. Most individuals have birth weights below the 25th centile.

• Weight remains below the fifth centile for age in about one third of affected individuals.
• Almost 60% of affected individuals have short stature (defined as height <5th centile for age and sex OR 2 SD below the mean for age and sex OR "postnatal growth failure").
  Bone age radiographs were abnormal (delayed, advanced, or disharmonic – i.e., different levels of maturation) in almost 65%.
• About one third of affected individuals have microcephaly (head circumference >5th centile for age OR 2 SD below the mean for age).

Gastrointestinal. About two thirds of affected individuals have a history of failure to thrive (FTT) and feeding difficulties, but fewer than one quarter require tube feeding. FTT can be transitory and nasogastric tube feedings can be temporarily useful. Constipation is present in about half of affected individuals and is more common in those with associated FTT.

Neurologic

• Sacral anomaly, most commonly a sacral dimple, was seen in about 45% of affected individuals. Other sacral anomalies include spina bifida occulta and tethered cord requiring surgery.
• Hypotonia is present in about two thirds of affected individuals.
  • Hypotonia can be present at birth and may lead to recommendation for a gastrostomy tube or nasogastric tube.
  • Some individuals continue to require supplemental nutrition through their gastrostomy tube.
  • Hypotonia appears to improve over time in some.
• Seizures are present in almost one fifth of affected individuals.
  • Seizure types include absence, partial complex epilepsy, eyelid myoclonia, tonic-clonic, febrile seizures, and infantile spasms [Helbig et al 2016].
  • Epileptic encephalopathy has also been reported.
  • Limited treatment information is available; however, multidrug resistance has been reported, and treatment with lamotrigine has been reported to be successful, although some affected individuals have not required treatment [Koenig et al 2010, Stellacci et al 2016, Baer et al 2018, Sheppard et al 2021].
• Central apnea has also been reported.

Brain MRI findings. A structural brain abnormality is present in about half of affected individuals who have undergone brain imaging. Examples of findings [Baer et al 2018, Sheppard et al 2021]:

• Abnormalities of the corpus callosum
• Abnormal myelination
• White matter changes, such as punctate foci of hyperintensity within the white matter, evidence of white matter volume loss, and paucity of white matter
• Chiari 1 malformation spectrum, which may include relatively narrow foramen magnum and platybasia
• Periventricular nodular heterotopia
• Choroid plexus cysts
• Abnormalities involving the pituitary gland, such as absent pituitary neurohypophysis, abnormal shape of the sella turcica, ectopic posterior bright spot with hypoplasia of hypothalamic pituitary axis, and pituitary hypoplasia (see Endocrinologic in this section)
• Cortical malformations, including bilateral frontal polymicrogyria [Grangeia et al 2020, Nardello et al 2021]
• Hypoplastic optic nerves [Chen et al 2019]
• Cerebrospinal fluid anomalies including aqueductal stenosis and third ventricle dilatation [Arora et al 2020]
• Cerebral atrophy
• Vermis hypoplasia [Di Fede et al 2021]
• Cerebellar atrophy [Giangiobbe et al 2020]

Integument/hair. Hypertrichosis is common, occurring in approximately 50%-75% of affected individuals, and includes:

• Eyebrows
• Long eyelashes
• Thick hair on the scalp
• Hypertrichosis of the back
• Hypertrichosis cubiti
• Hypertrichosis of the lower limbs

Skeletal/limb. Vertebral anomalies are the most common musculoskeletal finding, occurring in about half of affected individuals. Most of those who have vertebral anomalies have fusion in the cervical spine, most commonly at C2-C3, though some have abnormalities in the thoracic, lumbar, or sacral spine. Other skeletal anomalies include the following:

• Rib anomalies (e.g., reduced number of rib pairs, hypoplastic appearance of ribs, cervical ribs) are found in about one third of affected individuals.
• Broad first digits and/or tapering fingers are present in about one quarter of affected individuals, with some individuals having persistent fetal fingertip pads [Miyake et al 2016, Enokizono et al 2017, Wang et al 2021].
• Fewer than one fifth of affected individuals have scoliosis, which in rare cases can be severe enough to require surgery.
• Pectus excavatum has been described in a small number of affected individuals.
• Hip dysplasia has also been seen in a small number of affected individuals, although none of those with hip dysplasia were breech at birth.
  Several individuals required surgery and one required a Pavlik harness.
• One individual had scaphocephaly and another had metopic craniosynostosis [Nardello et al 2021]. The authors are also aware of a second individual with metopic craniosynostosis.

Cardiac. Cardiac abnormalities were present in about one third of those who underwent cardiac evaluation. Cardiac issues can include:

• Structural cardiac anomalies (patent ductus arteriosus, patent foramen ovale, right aortic arch, aortic insufficiency, bicuspid aortic valve, atrial septal defect, ventricular septal defect, tetralogy of Fallot, aberrant right subclavian artery, mitral valve prolapse, dextrocardia, mitral regurgitation, tricuspid regurgitation, overriding aorta, and thickened aortic valve)
• Arrhythmia (one affected individual required a pacemaker), including third-degree AV block [Bogaert et al 2017, Li et al 2018]
• Pulmonary hypertension
• Syncopal episodes

Genitourinary. Abnormalities in the genitourinary system are present in almost half of affected individuals.

• Renal anomaly was seen in about one quarter and included vesiculouretal reflux with hydronephrosis.
• Uterine or testicular anomalies were seen in almost 20%, including absent uterus in females and cryptorchidism in males.
• About 10% have an external genital anomaly, including prominent clitoris, underdeveloped scrotum, and hypospadias.

Eyes. A wide variety of ophthalmologic abnormalities are seen, including:

• Strabismus
• Astigmatism
• Hyperopia
• Myopia
• Amblyopia
• Lacrimal duct abnormalities
• Ptosis
• Rarely, cataract, coloboma, or glaucoma

ENT. Obstructive sleep apnea is the most common finding, occurring in about one quarter of affected individuals and necessitating tonsillectomy and adenoidectomy in close to 20% of those who have obstructive sleep apnea.

Dental/oral. More than half of affected individuals have a dental issue, the most common of which is advanced dental age characterized by premature loss of deciduous teeth and emergence of secondary teeth at an atypical earlier age. Other features include malocclusion, dysmorphic teeth, hypodontia, supernumerary teeth, poor enamel, caries, high-arched palate needing a palate expander, and gum issues.

Endocrinologic. Endocrine abnormalities include:

• Short stature (see Growth in this section)
• Premature adrenarche
• Menorrhagia, polycystic ovary syndrome, and/or irregular menses
• Abnormality of the pituitary gland seen on brain MRI (see Brain MRI findings in this section)
• Growth hormone (GH) deficiency, defined by low serum GH, IGF-1 or GH stimulation test
• Osteopenia
• Hypothyroidism (including congenital hypothyroidism and Hashimoto thyroiditis)
• Hypoparathyroidism

Immunologic issues have also been reported, including [Jones et al 2012, Stellacci et al 2016, Bogaert et al 2017, Baer et al 2018, Sheppard et al 2021]:

• Immunodeficiency, including common variable immunodeficiency
• Insufficient response to vaccinations
• History of recurrent infections
• Recurrent fevers of unknown origin
• Eosinophilia [Zhang et al 2019]

One boy had recurrent pulmonary infections and died of sepsis [Bramswig et al 2015].

Prognosis. It is unknown whether life span in WSS is abnormal. Multiple adults have been reported in the literature [Li et al 2018, Feldman et al 2019, Sheppard et al 2021]. While some adults do not work, one attended a daytime rehabilitation program, another owned a construction business, and another was currently in college managing without academic assistance. Adults with WSS could have affected children. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

Some genotype-phenotype correlations have been established.

• Individuals with loss-of-function variants in KMT2A are more likely to have hypotonia than those with non-loss-of-function variants [Sheppard et al 2021].
• In contrast, participants with non-loss-of-function variants are more likely to have seizures [Sheppard et al 2021].
• Missense variants in the CXXC DNA-binding domain (amino acids 1147-1195) may be associated with more significant neurodevelopmental issues [Min Ko et al 2017, Li et al 2018, Lebrun et al 2018].

Nomenclature

In 1970, Dr P Beighton described a father and two of his children with familial hypertrichosis cubiti or "hairy elbows" syndrome [Beighton 1970]. Subsequently, Dr HR Wiedemann and colleagues described a male with growth deficiency, developmental delay, strabismus, renal calyceal dilatation, and characteristic facial features [Wiedemann et al 1989]. In 2000, Dr CE Steiner and Dr AP Marques reported a female with features similar to those reported by Beighton and Wiedemann and suggested a common diagnosis [Steiner & Marques 2000]. Although "hairy elbows syndrome" has been used to describe WSS in some articles, "Wiedemann-Steiner syndrome" is now commonly used. Alternatively, KMT2A-related neurodevelopmental disorder can be used, following the naming system proposed by Biesecker et al [2021].

Prevalence

The prevalence of WSS is not known. Almost 250 individuals have been reported in the literature. Multiple adults were diagnosed as part of their child's evaluation, so it is possible that WSS could be underdiagnosed [Sheppard et al 2021].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with WSS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

The authors are aware of one individual with WSS who developed hyperammonemia with the use of the anti-seizure medication valproate. While this is not specific to individuals with WSS, valproate should be used with caution.

Evaluation of Relatives at Risk

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

Pregnancy Management

Some women with WSS have a seizure disorder that is treated with an anti-seizure medication. 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 during pregnancy reduces this risk. However, exposure to anti-seizure medication may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which the medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from anti-seizure medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of anti-seizure medication to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given anti-seizure medication 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].

Cervical spine anomalies may lead to immobility or instability, which may complicate airway management. Vertebral anomalies or scoliosis in the thoracic or lumbar spine may complicate spinal or epidural anesthesia.

Affected fetuses may be at risk for late prematurity, with average gestation ranging from 36 to 38 weeks [Baer et al 2018].

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

Wiedemann-Steiner syndrome (WSS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with WSS whose parents have undergone molecular genetic testing have the disorder as the result of a de novo pathogenic variant.
• Rarely, individuals diagnosed with WSS have an affected parent [Baer et al 2018, Sheppard et al 2021].
• If the proband appears to be the only affected family member (i.e., a simplex case), 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 apparently asymptomatic parent and parental identity testing has confirmed biological maternity and paternity, 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 a KMT2A pathogenic variant may be mildly/minimally affected [Baer et al 2018].
• The family history of some individuals diagnosed with WSS may appear to be negative because of failure to recognize the disorder in mildly affected family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish 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 pathogenic variant identified in the proband, the risk to the sibs is 50%.
• Clinical variability among affected sibs with the same pathogenic variant has been observed. In a family with six sibs with WSS, all had failure to thrive and feeding difficulties, there was a range of developmental delay, and some had structural malformations whereas others did not [Sheppard et al 2021].
• If the proband has a known KMT2A pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of germline mosaicism in a clinically unaffected parent. Mosaicism for a KMT2A pathogenic variant in a clinically unaffected parent has been described in one family [Baer et al 2018].
• If the parents are clinically unaffected after a thorough evaluation for subtle findings but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with WSS has a 50% chance of inheriting the KMT2A 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 pathogenic variant, members of the parent's family 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 KMT2A 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

The KMT2A gene product is a DNA-binding protein that methylates histone H3 and thereby regulates expression of numerous target genes.

KMT2A is the mammalian homolog of Drosophila Trithorax, which regulates Hox expression. KMT2A is important in hematopoiesis and axial skeletal patterning [Hess et al 1997].

Mechanism of disease causation. KMT2A pathogenic nonsense variants lead to nonsense-mediated decay, suggesting haploinsufficiency as the mechanism [Jones et al 2012]. The pathogenesis of missense variants may vary by the location, though preliminary studies suggest decreased expression of target genes. The CXXC domain is thought to be important for binding to target genes and the TAD domain is important for transcriptional activation. A missense variant in the CXXC domain (c.3460C>T; p.Arg1154Trp) resulted in overexpression of the KMT2A transcript and reduction of downstream target genes SIX2 and MEIS1, suggestive of impaired DNA binding. Conversely, a missense variant in the TAD domain (c.8558T>G; p.Met2853Trp) did not lead to significant changes in transcript level, but also resulted in a significant reduction in SIX2 and MEIS1 transcript, suggesting an issue with transcriptional activation [Lebrun et al 2018].

Cancer and Benign Tumors

About 10% of all pediatric and adult leukemias are caused by more than 90 different fusions involving KMT2A, which are thought to lead to disordered epigenetic regulation and thus abnormal gene transcription [Winters & Bernt 2017, Meyer et al 2018].

There is a single report of a family including three sibs with primary mediastinal large B-cell lymphoma and their cousin with diffuse large B-cell lymphoma, both subtypes of non-Hodgkin lymphoma, with a variant in KMT2A (referred to as MLL 5533C>A [His1845Asn] in the article) discovered via exome sequencing. This variant was also found in three healthy family members. The variant was not found in 86 healthy Finnish controls, 92 sporadic non-Hodgkin lymphoma cases, or 14 familial non-Hodgkin lymphoma cases that were screened [Saarinen et al 2013].

Acknowledgments

We thank the participants and their families and our co-authors [Sheppard et al 2021]. This work was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number TL1TR001880 (S.E.S.). Figures included in this chapter are adapted from Sheppard et al [2021].

Revision History

• 26 May 2022 (ma) Review posted live
• 3 August 2021 (fqr) Original submission

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