Browsing by Author "Abad C."
  • Institution Publication
    Bromodomain Protein BRD4 Is Essential for Hair Cell Function and Survival
    ( 2020-09-08)
    Kannan-Sundhari A.
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    Kannan-Sundhari A.
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    Abad C.
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    Maloof M.E.
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    Ayad N.G.
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    Young J.I.
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    Young J.I.
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    Liu X.Z.
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    Liu X.Z.
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    Liu X.Z.
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    Walz K.
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    Walz K.
    Hair cells (HCs) play crucial roles in perceiving sound, acceleration, and fluid motion. The tonotopic architecture of the sensory epithelium recognizes mechanical stimuli and convert them into electrical signals. The expression and regulation of the genes in the inner ear is very important to keep the sensory organ functional. Our study is the first to investigate the role of the epigenetic reader Brd4 in the mouse inner ear. We demonstrate that HC specific deletion of Brd4 in vivo in the mouse inner ear is sufficient to cause profound hearing loss (HL), degeneration of stereocilia, nerve fibers and HC loss postnatally in mouse; suggesting an important role in hearing function and maintenance.
  • Institution Publication
    Carboxypeptidase D deficiency causes hearing loss amenable to treatment
    ( 2025-01-01)
    Ramzan M.
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    Ortiz-Vega N.
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    Ortiz-Vega N.
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    Zafeer M.F.
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    Lobato A.G.
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    Lobato A.G.
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    Atik T.
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    Abad C.
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    Vadgama N.
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    Duman D.
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    Duman D.
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    Bozan N.
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    Durmuşalioǧlu E.A.
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    Greene S.
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    Guo S.
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    Tokgöz-Yılmaz S.
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    Yekedüz M.K.
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    Yekedüz M.K.
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    EminoÄŸlu F.T.
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    EminoÄŸlu F.T.
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    Aydın M.
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    Seyhan S.
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    Karakikes I.
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    Camarena V.
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    Robayo M.C.
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    Canic T.
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    Bademci G.
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    Wang G.
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    Wang G.
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    Farooq A.
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    Joiner M.l.
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    Walz K.
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    Walz K.
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    Walz K.
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    Eberl D.F.
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    Nasir J.
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    Zhai R.G.
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    Zhai R.G.
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    Tekin M.
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    Tekin M.
    Genetic factors contributing to hearing loss (HL) are heterogeneous, and effective medical treatments remain limited. We identified 3 distinct missense variants in CPD, encoding carboxypeptidase D, in 5 individuals with congenital deafness from 3 unrelated families, affecting the catalytically active CP domain 2 of this protein. Subsequent analysis of a larger cohort from the 100,000 Genomes Project revealed an enrichment of rare protein-altering CPD variants in individuals with HL. We show that CPD localizes to sensory epithelium and nerve cells in the mouse cochlea, and the enzymatic activity of CPD, crucial for nitric oxide (NO) production through arginine processing, is impaired in affected individuals. The levels of arginine, NO, and cGMP in patient-derived fibroblasts are also decreased, leading to endoplasmic reticulum stress–mediated responses being triggered in the cells. Silencing of Cpd in organotypic mouse cochlea cultures leads to increased apoptosis. Finally, Drosophila models of CPD deficiency display defective Johnston's organ, impaired auditory transduction, and sensory and movement abnormalities. Notably, these phenotypes are partially rescued by supplementation with arginine or sildenafil, a cGMP enhancer. Our findings establish CPD mutations as a cause of congenital HL, highlighting that the NO signaling pathway offers a promising therapeutic avenue.
  • Institution Publication
    Characterization of ANKRD11 mutations in humans and mice related to KBG syndrome
    ( 2015-01-13)
    Walz K.
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    Walz K.
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    Cohen D.
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    Neilsen P.M.
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    Foster J.
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    Brancati F.
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    Brancati F.
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    Demir K.
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    Fisher R.
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    Moffat M.
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    Verbeek N.E.
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    Bjørgo K.
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    Lo Castro A.
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    Curatolo P.
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    Novelli G.
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    Abad C.
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    Lei C.
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    Zhang L.
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    Diaz-Horta O.
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    Young J.I.
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    Callen D.F.
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    Tekin M.
    Mutations in ANKRD11 have recently been reported to cause KBG syndrome, an autosomal dominant condition characterized by intellectual disability (ID), behavioral problems, and macrodontia. To understand the pathogenic mechanism that relates ANKRD11 mutations with the phenotype of KBG syndrome, we studied the cellular characteristics of wild-type ANKRD11 and the effects of mutations in humans and mice. We show that the abundance of wild-type ANKRD11 is tightly regulated during the cell cycle, and that the ANKRD11 C-terminus is required for the degradation of the protein. Analysis of 11 pathogenic ANKRD11 variants in humans, including six reported in this study, and one reported in the Ankrd11Yod/+ mouse, shows that all mutations affect the C-terminal regions and that the mutant proteins accumulate aberrantly. In silico analysis shows the presence of D-box sequences that are signals for proteasome degradation. We suggest that ANKRD11 C-terminus plays an important role in regulating the abundance of the protein, and a disturbance of the protein abundance due to the mutations leads to KBG syndrome.
  • Institution Publication
    Disruption of Mbd5 in mice causes neuronal functional deficits and neurobehavioral abnormalities consistent with 2q23.1 microdeletion syndrome
    ( 2014-01-01)
    Camarena V.
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    Cao L.
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    Abad C.
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    Abrams A.
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    Toledo Y.
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    Araki K.
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    Araki M.
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    Walz K.
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    Walz K.
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    Young J.
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    Young J.
    2q23.1 microdeletion syndrome is characterized by intellectual disability, motor delay, autistic-like behaviors, and a distinctive craniofacial phenotype. All patients carry a partial or total deletion of methyl-CpG-binding domain protein 5 (MBD5), suggesting that haploinsufficiency of this gene is responsible for the phenotype. To confirm this hypothesis and to examine the role of MBD5 in vivo, we have generated and characterized an Mbd5 gene-trap mouse model. Our study indicates that the Mbd5+/GT mouse model recapitulates most of the hallmark phenotypes observed in 2q23.1 deletion carriers including abnormal social behavior, cognitive impairment, and motor and craniofacial abnormalities. In addition, neuronal cultures uncovered a deficiency in neurite outgrowth. These findings support a causal role of MBD5 in 2q23.1 microdeletion syndrome and suggest a role for MBD5 in neuronal processes. The Mbd5+/GT mouse model will advance our understanding of the abnormal brain development underlying the emergence of 2q23.1 deletion-associated behavioral and cognitive symptoms. © 2014 The Authors.
  • Institution Publication
    Identification of an IGSF3 mutation in a family with congenital nasolacrimal duct obstruction
    ( 2014-12-01)
    Foster J.
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    Kapoor S.
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    Diaz-Horta O.
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    Singh A.
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    Abad C.
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    Rastogi A.
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    Moharana R.
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    Tekeli O.
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    Walz K.
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    Tekin M.
  • Institution Publication
    SORD-deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights
    ( 2024-09-01)
    Rebelo A.P.
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    Abad C.
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    Dohrn M.F.
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    Dohrn M.F.
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    Li J.J.
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    Tieu E.K.
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    Medina J.
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    Yanick C.
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    Huang J.
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    Zotter B.
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    Young J.I.
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    Saporta M.
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    Scherer S.S.
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    Walz K.
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    Walz K.
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    Zuchner S.
    Biallelic SORD mutations cause one of the most frequent forms of recessive hereditary neuropathy, estimated to affect ∼10 000 patients in North America and Europe alone. Pathogenic SORD loss-of-function changes in the encoded enzyme sorbitol dehydrogenase result in abnormally high sorbitol levels in cells and serum. How sorbitol accumulation leads to peripheral neuropathy remains to be elucidated. A reproducible animal model for SORD neuropathy is essential to illuminate the pathogenesis of SORD deficiency and for preclinical studies of potential therapies. Therefore, we have generated a Sord knockout (KO), Sord-/-, Sprague Dawley rat, to model the human disease and to investigate the pathophysiology underlying SORD deficiency. We have characterized the phenotype in these rats with a battery of behavioural tests as well as biochemical, physiological and comprehensive histological examinations. Sord-/- rats had remarkably increased levels of sorbitol in serum, CSF and peripheral nerve. Moreover, serum from Sord-/- rats contained significantly increased levels of neurofilament light chain, an established biomarker for axonal degeneration. Motor performance significantly declined in Sord-/- animals starting at ∼7 months of age. Gait analysis evaluated with video motion-Tracking confirmed abnormal gait patterns in the hindlimbs. Motor nerve conduction velocities of the tibial nerves were slowed. Light and electron microscopy of the peripheral nervous system revealed degenerating myelinated axons, de-and remyelinated axons, and a likely pathognomonic finding-enlarged 'ballooned' myelin sheaths. These findings mainly affected myelinated motor axons; myelinated sensory axons were largely spared. In summary, Sord-/- rats develop a motor-predominant neuropathy that closely resembles the human phenotype. Our studies revealed novel significant aspects of SORD deficiency, and this model will lead to an improved understanding of the pathophysiology and the therapeutic options for SORD neuropathy.
  • Institution Publication
    Transcriptional consequences of MBD5 disruption in mouse brain and CRISPR-derived neurons
    ( 2020-06-05)
    Seabra C.M.
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    Seabra C.M.
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    Seabra C.M.
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    Aneichyk T.
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    Aneichyk T.
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    Aneichyk T.
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    Erdin S.
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    Erdin S.
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    Tai D.J.C.
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    Tai D.J.C.
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    Tai D.J.C.
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    De Esch C.E.F.
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    De Esch C.E.F.
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    De Esch C.E.F.
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    Razaz P.
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    Razaz P.
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    Razaz P.
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    An Y.
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    An Y.
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    Manavalan P.
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    Ragavendran A.
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    Ragavendran A.
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    Ragavendran A.
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    Stortchevoi A.
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    Abad C.
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    Young J.I.
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    MacIel P.
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    MacIel P.
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    Talkowski M.E.
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    Talkowski M.E.
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    Talkowski M.E.
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    Gusella J.F.
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    Gusella J.F.
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    Gusella J.F.
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    Gusella J.F.
    Background: MBD5, encoding the methyl-CpG-binding domain 5 protein, has been proposed as a necessary and sufficient driver of the 2q23.1 microdeletion syndrome. De novo missense and protein-truncating variants from exome sequencing studies have directly implicated MBD5 in the etiology of autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDDs). However, little is known concerning the specific function(s) of MBD5. Methods: To gain insight into the complex interactions associated with alteration of MBD5 in individuals with ASD and related NDDs, we explored the transcriptional landscape of MBD5 haploinsufficiency across multiple mouse brain regions of a heterozygous hypomorphic Mbd5 +/GT mouse model, and compared these results to CRISPR-mediated mutations of MBD5 in human iPSC-derived neuronal models. Results: Gene expression analyses across three brain regions from Mbd5 +/GT mice showed subtle transcriptional changes, with cortex displaying the most widespread changes following Mbd5 reduction, indicating context-dependent effects. Comparison with MBD5 reduction in human neuronal cells reinforced the context-dependence of gene expression changes due to MBD5 deficiency. Gene co-expression network analyses revealed gene clusters that were associated with reduced MBD5 expression and enriched for terms related to ciliary function. Limitations: These analyses included a limited number of mouse brain regions and neuronal models, and the effects of the gene knockdown are subtle. As such, these results will not reflect the full extent of MBD5 disruption across human brain regions during early neurodevelopment in ASD, or capture the diverse spectrum of cell-type-specific changes associated with MBD5 alterations. Conclusions: Our study points to modest and context-dependent transcriptional consequences of Mbd5 disruption in the brain. It also suggests a possible link between MBD5 and perturbations in ciliary function, which is an established pathogenic mechanism in developmental disorders and syndromes.