Unique profile of academic learning difficulties in Wiedemann-Steiner syndrome.

BACKGROUND: Wiedemann-Steiner syndrome (WSS) is a rare genetic disorder caused by heterozygous variants in KMT2A. To date, the cognitive profile associated with WSS remains largely unknown, although emergent case series implicate increased risk of non-verbal reasoning and visual processing deficits. This study examines the academic and learning concerns associated with WSS based on a parent-report screening measure. PARTICIPANTS AND METHODS: A total of 25 parents of children/adults with a molecularly-confirmed diagnosis of WSS (mean age = 12.85 years, SD = 7.82) completed the Colorado Learning Difficulties Questionnaire (CLDQ), a parent-screening measure of learning and academic difficulties. Parent ratings were compared to those from a normative community sample to determine focal areas in Math, Reading and Spatial skills that may be weaker within this clinical population. RESULTS: On average, parent ratings on the Math (mean Z = -3.08, SD = 0.87) and Spatial scales (mean Z = -2.52, SD = 0.85) were significantly more elevated than that of Reading (mean Z = -1.31, SD = 1.46) (Wilcoxon sign rank test Z < -3.83, P < 0.001), reflecting relatively more challenges observed in these areas. Distribution of parent ratings in Math items largely reflect a positively skewed distribution with most endorsing over three standard deviations below a community sample. In contrast, distributions of parent ratings in Reading and Spatial domains were more symmetric but flat. Ratings for Reading items yielded much larger variance than the other two domains, reflecting a wider range of performance variability. CONCLUSIONS: Parent ratings on the CLDQ suggest more difficulties with Math and Spatial skills among those with WSS within group and relative to a community sample. Study results are consistent with recent case reports on the neuropsychological profile associated with WSS and with Kabuki syndrome, which is caused by variants in the related gene KMT2D. Findings lend support for overlapping cognitive patterns across syndromes, implicating potential common disease pathogenesis.

Neurocognitive and neurobehavioral characterization of two frequent forms of neurodevelopmental disorders: the DYRK1A and the Wiedemann-Steiner syndromes.

DYRK1A and Wiedemann-Steiner syndromes (WSS) are two genetic conditions associated with neurodevelopmental disorders (NDDs). Although their clinical phenotype has been described, their behavioral phenotype has not systematically been studied using standardized assessment tools. To characterize the latter, we conducted a retrospective study, collecting data on developmental history, autism spectrum disorder (ASD), adaptive functioning, behavioral assessments, and sensory processing of individuals with these syndromes (n = 14;21). In addition, we analyzed information collected from families (n = 20;20) using the GenIDA database, an international patient-driven data collection aiming to better characterize natural history of genetic forms of NDDs. In the retrospective study, individuals with DYRK1A syndrome showed lower adaptive behavior scores compared to those with WSS, whose scores showed greater heterogeneity. An ASD diagnosis was established for 57% (8/14) of individuals with DYRK1A syndrome and 24% (5/21) of those with WSS. Language and communication were severely impaired in individuals with DYRK1A syndrome, which was also evident from GenIDA data, whereas in WSS patients, exploration of behavioral phenotypes revealed the importance of anxiety symptomatology and ADHD signs, also flagged in GenIDA. This study, describing the behavioral and sensorial profiles of individuals with WSS and DYRK1A syndrome, highlighted some specificities important to be considered for patients' management.

Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome.

Wiedemann-Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the KMT2A gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies (typical or not) and other associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Interpretation and classification of rare KMT2A variants can be challenging. A genome-wide DNA methylation episignature for KMT2A-related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from KMT2A mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease.

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.

Expanding the phenotypic and genotypic spectrum of Wiedemann-Steiner syndrome: First patient from India.

Wiedemann-Steiner syndrome (WWS) is a rare disorder characterized by hypotonia, postnatal growth restriction, striking facial dysmorphism, and hirsutism. It is caused by heterozygous pathogenic variants in KMT2A. This gene has an established role in histone methylation, which explains the overlap of WWS with syndromes caused by genes involved in chromatin remodeling. We describe an infant with a novel single base pair deletion in KMT2A with features consistent with WWS, as well as additional features of stenosis of aqueduct of Sylvius and broad toes. The usefulness of Face2Gene as a tool for identification of dysmorphology syndromes is discussed, as in this patient, it suggested WWS as the top candidate disorder. To the best of our knowledge, this is the first patient of WWS reported from India, with a novel genotype and expanded phenotype.

Expanding the phenotype of Wiedemann-Steiner syndrome: Craniovertebral junction anomalies.

Wiedemann-Steiner syndrome (WDSTS) is a rare autosomal dominant condition caused by heterozygous loss of function variants in the KMT2A (MLL) gene, encoding a lysine N-methyltransferase that mediates a histone methylation pattern specific for epigenetic transcriptional activation. WDSTS is characterized by a distinctive facial phenotype, hypertrichosis, short stature, developmental delay, intellectual disability, congenital malformations, and skeletal anomalies. Recently, a few patients have been reported having abnormal skeletal development of the cervical spine. Here we describe 11 such individuals, all with KMT2A de novo loss-of-function variants: 10 showed craniovertebral junction anomalies, while an 11th patient had a cervical abnormality in C7. By evaluating clinical and diagnostic imaging data we characterized these anomalies, which consist primarily of fused cervical vertebrae, C1 and C2 abnormalities, small foramen magnum and Chiari malformation type I. Craniovertebral anomalies in WDSTS patients have been largely disregarded so far, but the increasing number of reports suggests that they may be an intrinsic feature of this syndrome. Specific investigation strategies should be considered for early identification and prevention of craniovertebral junction complications in WDSTS patients.

The progression of Wiedemann-Steiner syndrome in adulthood and two novel variants in the KMT2A gene.

Wiedemann-Steiner syndrome is a genetic condition associated with dysmorphic facies, hypertrichosis, short stature, developmental delay, and intellectual disability. Congenital malformations of the cerebral, cardiac, renal, and optic structures have also been reported. Because the majority of reported individuals with this condition have been under age 20, the long-term prognosis is not well defined. Here we report on two further unrelated individuals diagnosed with Wiedemann-Steiner syndrome, one of whom is in her third decade of life. In addition, both individuals have novel KMT2A mutations. The information provided below about the outcome in Wiedemann-Steiner syndrome is important for families of affected individuals.

A novel de novo mutation (p.Pro1310Glnfs*46) in KMT2A caused Wiedemann-Steiner Syndrome in a Chinese boy with postnatal growth retardation: a case report.

Wiedemann-Steiner Syndrome (WSS) is a very rare autosomal dominant disease. Mutations in the KMT2A gene have been shown to cause this disease. A 1-year-old Chinese boy exhibited growth delay, psychomotor retardation, limb hypotonia and facial dysmorphism that was consistent with WSS. His body weight started to drop below the normal range at 3 months old, and the decline persisted. Whole-exome sequencing showed a novel de novo mutation (p.Pro1310Glnfs*46) in KMT2A, which confirmed the diagnosis of WSS. We diagnosed a Chinese boy who presented postnatal growth retardation with WSS caused by a novel de novo mutation in KMT2A. Our findings expand the mutational and phenotypic spectra of WSS and will be valuable for the mutation-based pre- and postnatal screening for and genetic diagnosis of WSS.

TASP1 is deleted in an infant with developmental delay, microcephaly, distinctive facial features, and multiple congenital anomalies.

We report a 20p12.1 homozygous deletion including exons 5-10 of the TASP1 gene in an infant with developmental delay, acquired microcephaly, distinctive facial features, and multiple congenital anomalies involving skeletal, cardiac, and renal systems. TASP1 encodes taspase 1 which is responsible for cleaving, thus activating, a number of transcription factors including the mixed lineage leukemia 1 (MLL1). Taspase 1-deficient mice showed early lethality, skeletal abnormalities, and growth failure, which support a potentially causal role of TASP1 deletion in this infant. Furthermore, the infant reported here had many of the features seen in Wiedemann-Steiner syndrome which is caused by MLL1 defects. Such observation further supports that TASP1 is a novel disease-related gene that is associated with a disease phenotype overlapping with Wiedemann-Steiner syndrome as both are caused by defects in the same pathway.

Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases.

Wiedemann-Steiner syndrome (WSS) is a rare syndromic condition in which intellectual disability (ID) is associated with hypertrichosis cubiti, short stature, and characteristic facies. Following the identification of the causative gene (KMT2A) in 2012, only 31 cases of WSS have been described precisely in the literature. We report on 33 French individuals with a KMT2A mutation confirmed by targeted gene sequencing, high-throughput sequencing or exome sequencing. Patients' molecular and clinical features were recorded and compared with the literature data. On the molecular level, we found 29 novel mutations. We observed autosomal dominant transmission of WSS in 3 families and mosaicism in one family. Clinically, we observed a broad phenotypic spectrum with regard to ID (mild to severe), the facies (typical or not of WSS) and associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Hypertrichosis cubiti that was supposed to be pathognomonic in the literature was found only in 61% of our cases. This is the largest series of WSS cases yet described to date. A majority of patients exhibited suggestive features, but others were less characteristic, only identified by molecular diagnosis. The prevalence of WSS was higher than expected in patients with ID, suggesting than KMT2A is a major gene in ID.

Preaxial polydactyly in an individual with Wiedemann-Steiner syndrome caused by a novel nonsense mutation in KMT2A.

Wiedemann-Steiner syndrome (WDSTS) is an autosomal dominant disorder characterized by hypertrichosis, intellectual disability, and dysmorphic facial appearances (down-slanted vertically narrow palpebral fissures, wide nasal bridge, broad nasal tip, and thick eyebrows). In 2012, Jones and co-workers identified heterozygous mutations in KMT2A (lysine methyltransferase 2A) as the molecular cause of WDSTS. Although the phenotype of this syndrome continues to expand, the associated features are not fully understood. Here, we report WDSTS in a 12-year-old Japanese boy with a novel nonsense mutation in KMT2A. He had right preaxial polydactyly, which has not been previously reported in WDSTS. We could not identify a causal relationship between the KMT2A mutation and preaxial polydactyly, and cannot exclude the preaxial polydactyly is a simple coincidence. We summarized the clinical features of WDSTS associated with KMT2A mutation and discussed the cardinal symptoms in detail.

Further delineation of the phenotype of truncating KMT2A mutations: The extended Wiedemann-Steiner syndrome.

KMT2A mutations cause Wiedemann-Steiner syndrome (WDSTS), which is characterized by hypertrichosis cubiti, short stature, and distinct facial features in general. Here, we report two Chinese boys with novel nonsense KMT2A mutations. Most of their phenotypes are concordant with WDSTS. They, however, lack the key WDSTS feature-hypertrichosis cubiti. Additionally, their transverse palmar creases are absent. We further summarized the genotypes and phenotypes of the KMT2A mutation carriers. The consensus phenotypes include postnatal growth retardation, developmental delay, short stature, and intellectual disability. The common facial features include thick eyebrows, long eyelashes, downslanting, and narrow palpebral fissures, wide nasal bridge, and broad nasal tip. They have generalized hypertrichosis. A hairy back can be observed as frequently as hairy elbows in patients with KMT2A mutations. Absent palmar proximal transverse creases are only observed in these two Chinese boys. This might be due to the difference in ethnic background. Thus far, all mutations in KMT2A are located before the FYRC domain. They would truncate KMT2A mRNA transcripts. Haploinsufficiency of the histone methyltransferase activity would therefore influence transcriptional regulation. © 2016 Wiley Periodicals, Inc.

Delineation of clinical features in Wiedemann-Steiner syndrome caused by KMT2A mutations.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant congenital anomaly syndrome characterized by hairy elbows, dysmorphic facial appearances (hypertelorism, thick eyebrows, downslanted and vertically narrow palpebral fissures), pre- and post-natal growth deficiency, and psychomotor delay. WSS is caused by heterozygous mutations in KMT2A (also known as MLL), a gene encoding a histone methyltransferase. Here, we identify six novel KMT2A mutations in six WSS patients, with four mutations occurring de novo. Interestingly, some of the patients were initially diagnosed with atypical Kabuki syndrome, which is caused by mutations in KMT2D or KDM6A, genes also involved in histone methylation. KMT2A mutations and clinical features are summarized in our six patients together with eight previously reported patients. Furthermore, clinical comparison of the two syndromes is discussed in detail.

A de novo Mutation in KMT2A (MLL) in monozygotic twins with Wiedemann-Steiner syndrome.

Growth deficiency, psychomotor delay, and facial dysmorphism was originally described in a male patient in 1989 by Wiedemann et al. and later in 2000 by Steiner et al. Wiedemann-Steiner syndrome (WSS) has since been described only a few times in the literature, with the phenotypic spectrum both expanding and becoming more delineated with each patient reported. We report on the clinical and molecular features of monozygotic twins with a de novo mutation in KMT2A. Single nucleotide polymorphism (SNP) microarray was done on both twins and whole-exome sequencing was done using both parents and one of the affected twins. SNP microarray confirmed that they were monozygotic twins. A de novo heterozygous variant (p. Arg1083*) in the KMT2A gene was identified through whole-exome sequencing, confirming the diagnosis of WSS. In this study, we have identified a de novo mutation in KMT2A associated with psychomotor developmental delay, facial dysmorphism, short stature, hypertrichosis cubiti, and small kidneys. This finding in monozygotic twins gives specificity to the WSS. The description of more cases of WSS is needed for further delineation of this condition. Small kidneys with normal function have not been described in this condition in the medical literature before.

Aberrant splicing caused by a novel KMT2A variant in Wiedemann-Steiner syndrome.

INTRODUCTION: Wiedemann-Steiner syndrome (WSS) is a rare autosomal-dominant disorder caused by KMT2A variants. The aim of this study was to characterize a novel KMT2A variant in a child with WSS and demonstrate integrated diagnostic approaches. METHODS: A 3-year-old female with developmental delay, distinctive facial features, and anal fistula underwent whole exome sequencing (WES). RNA analysis was performed to assess splicing effects caused by a novel variant. RESULTS: WES identified novel heterozygous KMT2A c.5664+6T>C variant initially classified as a variant of uncertain significance. RNA analysis provided evidence of aberrant splicing (exon 20 skipping), allowing reclassification to likely pathogenic. The patient exhibited typical WSS features along with a potential novel finding of anal fistula. CONCLUSION: This report describes a novel non-canonical splice site variant in KMT2A associated with WSS. RNA analysis was critical for variant reclassification. Detailed phenotypic evaluation revealed common and expanded WSS manifestations. This case highlights the importance of combining clinical assessment, DNA testing, and RNA functional assays for the diagnosis of rare genetic disorders.

Uncovering a Genetic Diagnosis in a Pediatric Patient by Whole Exome Sequencing: A Modeling Investigation in Wiedemann-Steiner Syndrome.

Background: Wiedemann-Steiner syndrome (WSS), a rare autosomal-dominant disorder caused by haploinsufficiency of the KMT2A gene product, is part of a group of disorders called chromatinopathies. Chromatinopathies are neurodevelopmental disorders caused by mutations affecting the proteins responsible for chromatin remodeling and transcriptional regulation. The resulting gene expression dysregulation mediates the onset of a series of clinical features such as developmental delay, intellectual disability, facial dysmorphism, and behavioral disorders. Aim of the Study: The aim of this study was to investigate a 10-year-old girl who presented with clinical features suggestive of WSS. Methods: Clinical and genetic investigations were performed. Whole exome sequencing (WES) was used for genetic testing, performed using Illumina technology. The bidirectional capillary Sanger resequencing technique was used in accordance with standard methodology to validate a mutation discovered by WES in all family members who were available. Utilizing computational protein modeling for structural and functional studies as well as in silico pathogenicity prediction models, the effect of the mutation was examined. Results: WES identified a de novo heterozygous missense variant in the KMT2A gene KMT2A(NM_001197104.2): c.3451C>G, p.(Arg1151Gly), absent in the gnomAD database. The variant was classified as Likely Pathogenetic (LP) according to the ACMG criteria and was predicted to affect the CXXC-type zinc finger domain functionality of the protein. Modeling of the resulting protein structure suggested that this variant changes the protein flexibility due to a variation in the Gibbs free energy and in the vibrational entropy energy difference between the wild-type and mutated domain, resulting in an alteration of the DNA binding affinity. Conclusions: A novel and de novo mutation discovered by the NGS approach, enhancing the mutation spectrum in the KMT2A gene, was characterized and associated with WSS. This novel KMT2A gene variant is suggested to modify the CXXC-type zinc finger domain functionality by affecting protein flexibility and DNA binding.

Associations Between Executive Functioning, Behavioral Functioning, and Adaptive Functioning Difficulties in Wiedemann-Steiner Syndrome.

OBJECTIVES: Wiedemann-Steiner syndrome (WSS) is a neurogenetic disorder caused by heterozygous variants in KMT2A. Recent investigations suggest increased anxiety and behavior regulation challenges among those with WSS although the neurobehavioral phenotype remains largely unknown. This study aims to examine the pattern of and associations between executive functioning (EF) and behavior functioning among those with WSS. METHOD: This study involved utilizing caregiver-report inventories (Behavior Rating Inventory of Executive Function 2nd Edition, BRIEF-2; Adaptive Behavior Assessment 3rd Edition, ABAS-3; Strengths and Difficulties Questionnaire, SDQ) to assess day-to-day behavior functioning among those with WSS (N = 24; mean age = 10.68 years, SD = 3.19). Frequency of clinical elevations in daily difficulties in EF, adaptive behaviors, and behavior regulation were reported. Correlations and hierarchical linear regressions were used to determine the relationships between EF with behavior and adaptive functioning. RESULTS: Out of our sample, 63% met clinical levels of executive functioning difficulties on the BRIEF-2, and 75% with Hyperactivity and 54% with Emotional Problems on the SDQ. In addition, 33% were rated >2 SD below the normative mean in overall adaptive functioning on the ABAS-3. Elevated ratings in BRIEF-2 Shift, reflective of challenges with mental flexibility, predicted more Emotional Problems and accounted for 33.5% of its variance. More difficulties in Emotional Control were related to greater adaptive deficits, accounting for 33.3% of its variance. CONCLUSIONS: Those with WSS are at risk for EF deficits, hyperactivity, and emotional dysregulation. EF correlates with adaptive and affective behaviors, highlighting the promise of behavioral interventions to target cognitive flexibility, emotional awareness, and reactivity in this population.

Variants in KMT2A in Three Individuals with Previous Suspicion of 22q11.2 Deletion Syndrome.

The condition known as 22q11.2 deletion syndrome (MIM #188400) is a rare disease with a highly variable clinical presentation including more than 180 features; specific guidelines for screening individuals have been used to support clinical suspicion before confirmatory tests by Brazil's Craniofacial Project. Of the 2568 patients listed in the Brazilian Database on Craniofacial Anomalies, 43 individuals negative for the 22q11.2 deletion syndrome were further investigated through whole-exome sequencing. Three patients (6.7%) presented with heterozygous pathogenic variants in the KMT2A gene, including a novel variant (c.6158+1del) and two that had been previously reported (c.173dup and c.3241C>T); reverse phenotyping concluded that all three patients presented features of Wiedemann-Steiner syndrome, such as neurodevelopmental disorders and dysmorphic facial features (n = 3), hyperactivity and anxiety (n = 2), thick eyebrows and lower-limb hypertrichosis (n = 2), congenital heart disease (n = 1), short stature (n = 1), and velopharyngeal insufficiency (n = 2). Overlapping features between 22q11.2 deletion syndrome and Wiedemann-Steiner syndrome comprised neuropsychiatric disorders and dysmorphic characteristics involving the eyes and nose region; velopharyngeal insufficiency was seen in two patients and is an unreported finding in WDSTS. Therefore, we suggest that both conditions should be included in each other's differential diagnoses.

Diagnostic approach to a paediatric patient with Wiedemann-Steiner syndrome with de novo missense variant in the KMT2A gene - a case report.

INTRODUCTION: Wiedemann-Steiner syndrome is caused by mutations in the KMT2A gene (11q23.3). It might be inherited autosomal dominant or appear de novo. Features described in the syndrome include developmental delay, short stature, hypotonia, hypertrichosis, facial dysmorphic features, and intellectual disability. CASE REPORT: A boy aged 5.5 months was admitted to the Genetics Outpatient Clinic due to delayed psychomotor development. Microsomia, hypotonia, joint laxity, and facial dysmorphic features were noticed. No genomic imbalance was found in microarray, based on comparative genomic hybridization. The c.3528G>T variant of the KMT2A gene was identified on chromosome 11 of the missense type in next-generation sequencing. The reasons for phenotypic features were confirmed in genetic research. CONCLUSIONS: Wiedemann-Steiner syndrome has a variable clinical phenotype. There is a strong need to pay attention to phenotypic features that may suggest the syndrome and refer patients for appropriate genetic diagnostics.