KMT2A: Umbrella Gene for Multiple Diseases

Castiglioni, Silvia; Fede, Elisabetta Di; Bernardelli, Clara; Lettieri, Antonella; Parodi, Chiara; Grazioli, Paolo; Colombo, E.; Ancona, Silvia; Milani, Donatella; Ottaviano, Emerenziana; Borghi, Elisa; Massa, Valentina; Ghelma, Filippo; Lesma, Elena; Gervasini, Cristina

doi:10.3390/genes13030514

Cited by 31 publications

(26 citation statements)

References 103 publications

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“…A rare developmental disorder known as Kabuki syndrome (KS) is characterized by postnatal growth restriction, characteristic facial features (such as long palpebral fissures in the lateral third of the lower eyelids, arched and broad eyebrows with the lateral third displaying notches or sparseness, large, prominent, or cupped ears, and short columella with a depressed nasal tip), skeletal anomalies (such as brachymesophalangy, brachydactyly V, spinal column abnormalities, and fifth digit clinodactyly), dermatoglyphic abnormalities (persistent fingertip pads), and mild-to-moderate intellectual disability [ 36 ]. KS is primarily (60%) caused by mutations in KMT2D , or less often in KDM6A [ 36 , 37 ]. Cornelia De Lange syndrome (CdLS) is an archetypical genetic syndrome characterized by ID, distinctive facial features, malformations of the upper limbs, and atypical growth, among numerous other signs and symptoms.…”

Section: Discussionmentioning

confidence: 99%

Wiedemann–Steiner Syndrome: Case Report and Review of Literature

Zhang

et al. 2022

Children

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Wiedemann–Steiner syndrome (WDSTS) is an autosomal dominant disorder with a broad and variable phenotypic spectrum characterized by intellectual disability, prenatal and postnatal growth retardation, hypertrichosis, characteristic facial features, behavioral problems, and congenital anomalies involving different systems. Here, we report a five-year-old boy who was diagnosed with WDSTS based on the results of Trio-based whole-exome sequencing and an assessment of his clinical features. He had intellectual disability, short stature, hirsutism, and atypical facial features, including a low hairline, down-slanting palpebral fissures, hypertelorism, long eyelashes, broad and arching eyebrows, synophrys, a bulbous nose, a broad nasal tip, and dental/oral anomalies. However, not all individuals with WDSTS exhibit the classic phenotype, so the spectrum of the disorder can vary widely from relatively atypical facial features to multiple systemic symptoms. Here, we summarize the clinical and molecular spectrum, diagnosis and differential diagnosis, long-term management, and care planning of WDSTS to improve the awareness of both pediatricians and clinical geneticists and to promote the diagnosis and treatment of the disease.

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Section: Discussionmentioning

confidence: 99%

Wiedemann–Steiner Syndrome: Case Report and Review of Literature

Zhang

et al. 2022

Children

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“…Conversely, horseshoe kidney with/without pyelectasis was never reported in any SDS patient (PubMed and Google Scholar search, June 2022, using horseshoe kidney AND Shwachman-Diamond Syndrome), and is found in approximately 0.25% of the general population; moreover, it is more commonly reported in WDSTS, with six patients showing this malformation [ 40 , 49 , 59 , 60 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

Phenotypic Variation in Two Siblings Affected with Shwachman-Diamond Syndrome: The Use of Expert Variant Interpreter (eVai) Suggests Clinical Relevance of a Variant in the KMT2A Gene

Taha

Paoli²,

Foroni

et al. 2022

Genes

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Introduction. Shwachman-Diamond Syndrome (SDS) is an autosomal-recessive disorder characterized by neutropenia, pancreatic exocrine insufficiency, skeletal dysplasia, and an increased risk for leukemic transformation. Biallelic mutations in the SBDS gene have been found in about 90% of patients. The clinical spectrum of SDS in patients is wide, and variability has been noticed between different patients, siblings, and even within the same patient over time. Herein, we present two SDS siblings (UPN42 and UPN43) carrying the same SBDS mutations and showing relevant differences in their phenotypic presentation. Study aim. We attempted to understand whether other germline variants, in addition to SBDS, could explain some of the clinical variability noticed between the siblings. Methods. Whole-exome sequencing (WES) was performed. Human Phenotype Ontology (HPO) terms were defined for each patient, and the WES data were analyzed using the eVai and DIVAs platforms. Results. In UPN43, we found and confirmed, using Sanger sequencing, a novel de novo variant (c.10663G>A, p.Gly3555Ser) in the KMT2A gene that is associated with autosomal-dominant Wiedemann–Steiner Syndrome. The variant is classified as pathogenic according to different in silico prediction tools. Interestingly, it was found to be related to some of the HPO terms that describe UPN43. Conclusions. We postulate that the KMT2A variant found in UPN43 has a concomitant and co-occurring clinical effect, in addition to SBDS mutation. This dual molecular effect, supported by in silico prediction, could help to understand some of the clinical variations found among the siblings. In the future, these new data are likely to be useful for personalized medicine and therapy for selected cases.

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“…Large scale exome sequencing studies identified mutations in MLL1/KMT2A among patients presenting with developmental delay and ID (Deciphering Developmental Disorders Study, 2015;Lelieveld et al, 2016;Trujillano et al, 2017). Clinical genetics studies identified MLL1/KMT2A pathogenic variants in patients diagnosed with either Kabuki syndrome or Rubinstein-Taiby syndrome which are characterized by ID, postnatal growth defects and microcephaly (Sobreira et al, 2017;Castiglioni et al, 2022).…”

Section: Mll1/kmt2a a Central Contributor To The Pathogenesis Of Mult...mentioning

confidence: 99%

The role of histone methyltransferases in neurocognitive disorders associated with brain size abnormalities

Ritchie

Lizarraga

2023

Front. Neurosci.

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Brain size is controlled by several factors during neuronal development, including neural progenitor proliferation, neuronal arborization, gliogenesis, cell death, and synaptogenesis. Multiple neurodevelopmental disorders have co-morbid brain size abnormalities, such as microcephaly and macrocephaly. Mutations in histone methyltransferases that modify histone H3 on Lysine 36 and Lysine 4 (H3K36 and H3K4) have been identified in neurodevelopmental disorders involving both microcephaly and macrocephaly. H3K36 and H3K4 methylation are both associated with transcriptional activation and are proposed to sterically hinder the repressive activity of the Polycomb Repressor Complex 2 (PRC2). During neuronal development, tri-methylation of H3K27 (H3K27me3) by PRC2 leads to genome wide transcriptional repression of genes that regulate cell fate transitions and neuronal arborization. Here we provide a review of neurodevelopmental processes and disorders associated with H3K36 and H3K4 histone methyltransferases, with emphasis on processes that contribute to brain size abnormalities. Additionally, we discuss how the counteracting activities of H3K36 and H3K4 modifying enzymes vs. PRC2 could contribute to brain size abnormalities which is an underexplored mechanism in relation to brain size control.

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KMT2A: Umbrella Gene for Multiple Diseases

Cited by 31 publications

References 103 publications

Wiedemann–Steiner Syndrome: Case Report and Review of Literature

Wiedemann–Steiner Syndrome: Case Report and Review of Literature

Phenotypic Variation in Two Siblings Affected with Shwachman-Diamond Syndrome: The Use of Expert Variant Interpreter (eVai) Suggests Clinical Relevance of a Variant in the KMT2A Gene

The role of histone methyltransferases in neurocognitive disorders associated with brain size abnormalities

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