A three generation X‐linked family with Kabuki syndrome phenotype and a frameshift mutation in <i>KDM6A</i>

Lederer, Damien; Shears, Debbie; Benoît, Valérie; Verellen‐Dumoulin, Christine; Maystadt, Isabelle

doi:10.1002/ajmg.a.36442

Cited by 40 publications

(48 citation statements)

References 17 publications

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“…The finding of an intellectually normal female patient with KS2 is in line with the observation of Lederer et al. (), who described two mentally normal females, whose male offspring presented with intellectual disability.…”

Section: Methodssupporting

confidence: 90%

“…Lederer et al. () argued in the direction of a more pronounced phenotype in male patients, especially with regard to facial features and cognitive achievements, an observation also made by Banka et al. ().…”

Section: Methodsmentioning

confidence: 67%

“…Lederer et al. ) reported a three‐generation family with two affected boys whose mother and maternal grandmother were both carriers of a truncating KDM6A mutation and showed only few features reminiscent of KS but not the typical KS phenotype. Lederer et al.…”

Section: Methodsmentioning

confidence: 99%

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Mutation Update for Kabuki Syndrome GenesKMT2DandKDM6Aand Further Delineation of X-Linked Kabuki Syndrome Subtype 2

et al. 2016

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Kabuki syndrome (KS) is a rare but recognizable condition that consists of a characteristic face, short stature, various organ malformations, and a variable degree of intellectual disability. Mutations in KMT2D have been identified as the main cause for KS, whereas mutations in KDM6A are a much less frequent cause. Here, we report a mutation screening in a case series of 347 unpublished patients, in which we identified 12 novel KDM6A mutations (KS type 2) and 208 mutations in KMT2D (KS type 1), 132 of them novel. Two of the KDM6A mutations were maternally inherited and nine were shown to be de novo. We give an up-to-date overview of all published mutations for the two KS genes and point out possible mutation hot spots and strategies for molecular genetic testing. We also report the clinical details for 11 patients with KS type 2, summarize the published clinical information, specifically with a focus on the less well-defined X-linked KS type 2, and comment on phenotype-genotype correlations as well as sex-specific phenotypic differences. Finally, we also discuss a possible role of KDM6A in Kabuki-like Turner syndrome and report a mutation screening of KDM6C (UTY) in male KS patients.

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Section: Methodssupporting

confidence: 90%

Section: Methodsmentioning

confidence: 67%

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Mutation Update for Kabuki Syndrome GenesKMT2DandKDM6Aand Further Delineation of X-Linked Kabuki Syndrome Subtype 2

et al. 2016

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“…Nonetheless, rare CNVs detected by MLPA in KMT2D in 3 out of 64 patients were observed by others . In addition, we did not detect CNVs within KDM6A using MLPA, while others found partial or entire deletions of this gene .…”

Section: Discussioncontrasting

confidence: 72%

Molecular genetic analysis in 14 Czech Kabuki syndrome patients is confirming the utility of phenotypic scoring

et al. 2016

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Kabuki syndrome (KS) is a dominantly inherited disorder mainly due to de novo pathogenic variation in KMT2D or KDM6A genes. Initially, a representative cohort of 14 Czech cases with clinical features suggestive of KS was analyzed by experienced clinical geneticists in collaboration with other specialties, and observed disease features were evaluated according to the 'MLL2-Kabuki score' defined by Makrythanasis et al. Subsequently, the aforementioned genes were Sanger sequenced and copy number variation analysis was performed by MLPA, followed by genome-wide array CGH testing. Pathogenic variants in KMT2D resulting in protein truncation in 43% (6/14; of which 3 are novel) of all cases were detected, while analysis of KDM6A was negative. MLPA analysis was negative in all instances. One female patient bears a 6.6 Mb duplication of the Xp21.2-Xp21.3 region that is probably disease causing. Subjective KS phenotyping identified predictive clinical features associated with the presence of a pathogenic variant in KMT2D. We provide additional evidence that this scoring approach fosters prioritization of patients prior to KMT2D sequencing. We conclude that KMT2D sequencing followed by array CGH is a diagnostic strategy with the highest diagnostic yield.

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“…Misregulation of the pathways that control phosphate homeostasis in the body can lead to severe disorders, such as bone mineralization, soft tissue calcification, or renal lithiasis. The kidney plays a central role in this homeostasis by facilitating the reabsorption of phosphate in the proximal tubule; this reabsorption is mediated by transporters belonging to the solute carrier family SLC34, also known as NaPi-II cotransporters, which use the sodium-electrochemical gradient to drive phosphate translocation against its concentration gradient [5, 15, 25]. The three members of the SLC34 family, NaPi-IIa, b, and c, differ in their Na + :P i stoichiometry; members NaPi-IIa and NaPi-IIb are electrogenic and transport three sodium ions per phosphate molecule, while NaPi-IIc is electroneutral, transporting two sodium ions per phosphate [17].…”

Section: Introductionmentioning

confidence: 99%

Structural models of the NaPi-II sodium-phosphate cotransporters

Fenollar–Ferrer

Forrest

2018

Pflugers Arch - Eur J Physiol

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Progress towards understanding the molecular mechanisms of phosphate homeostasis through sodium-dependent transmembrane uptake has long been stymied by the absence of structural information about the NaPi-II sodium-phosphate transporters. For many other coupled transporters, even those unrelated to NaPi-II, internal repeated elements have been revealed as a key feature that is inherent to their function. Here, we review recent structure prediction studies for NaPi-II transporters. Attempts to identify structural templates for NaPi-II transporters have leveraged the structural repeat perspective to uncover an otherwise obscured relationship with the dicarboxylate-sodium symporters (DASS). This revelation allowed the prediction of three-dimensional structural models of human NaPi-IIa and flounder NaPi-IIb, whose folds were evaluated by comparison with available biochemical data outlining the transmembrane topology and solvent accessibility of various regions of the protein. Using these structural models, binding sites for sodium and phosphate were proposed. The predicted sites were tested and refined based on detailed electrophysiological and biochemical studies and were validated by comparison with subsequently reported structures of transporters belonging to the AbgT family. Comparison with the DASS transporter VcINDY suggested a conformational mechanism involving a large, two-domain structural change, known as an elevator-like mechanism. These structural models provide a foundation for further studies into substrate binding, conformational change, kinetics, and energetics of sodium-phosphate transport. We discuss future opportunities, as well as the challenges that remain.

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A three generation X‐linked family with Kabuki syndrome phenotype and a frameshift mutation in KDM6A

Cited by 40 publications

References 17 publications

Mutation Update for Kabuki Syndrome GenesKMT2DandKDM6Aand Further Delineation of X-Linked Kabuki Syndrome Subtype 2

Mutation Update for Kabuki Syndrome GenesKMT2DandKDM6Aand Further Delineation of X-Linked Kabuki Syndrome Subtype 2

Molecular genetic analysis in 14 Czech Kabuki syndrome patients is confirming the utility of phenotypic scoring

Structural models of the NaPi-II sodium-phosphate cotransporters

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