Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice.

Mutations in genes encoding chromatin modifiers are enriched among mutations causing intellectual disability. The continuing development of the brain postnatally, coupled with the inherent reversibility of chromatin modifications, may afford an opportunity for therapeutic intervention following a genetic diagnosis. Development of treatments requires an understanding of protein function and models of the disease. Here, we provide a mouse model of Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) (OMIM 603736) and demonstrate proof-of-principle efficacy of postnatal treatment. SBBYSS results from heterozygous mutations in the KAT6B (MYST4/MORF/QFK) gene and is characterized by intellectual disability and autism-like behaviors. Using human cells carrying SBBYSS-specific KAT6B mutations and Kat6b heterozygous mice (Kat6b+/-), we showed that KAT6B deficiency caused a reduction in histone H3 lysine 9 acetylation. Kat6b+/- mice displayed learning, memory, and social deficits, mirroring SBBYSS individuals. Treatment with a histone deacetylase inhibitor, valproic acid, or an acetyl donor, acetyl-carnitine (ALCAR), elevated histone acetylation levels in the human cells with SBBYSS mutations and in brain and blood cells of Kat6b+/- mice and partially reversed gene expression changes in Kat6b+/- cortical neurons. Both compounds improved sociability in Kat6b+/- mice, and ALCAR treatment restored learning and memory. These data suggest that a subset of SBBYSS individuals may benefit from postnatal therapeutic interventions.

Identification of potential molecular mechanism related to craniofacial dysmorphism caused by FOXI3 deficiency.

BACKGROUND: Hemifacial macrosomia (HFM, OMIM 164210) is a complex and highly heterogeneous disease. FORKHEAD BOX I3 (FOXI3) is a susceptibility gene for HFM, and mice with loss of function of Foxi3 did exhibit a phenotype similar to craniofacial dysmorphism. However, the specific pathogenesis of HFM caused by FOXI3 deficiency remains unclear till now. METHOD: In this study, we first constructed a Foxi3 deficiency (Foxi3-/- ) mouse model to verify the craniofacial phenotype of Foxi3-/- mice, and then used RNAseq data for gene differential expression analysis to screen candidate pathogenic genes, and conducted gene expression verification analysis using quantitative real-time PCR. RESULTS: By observing the phenotype of Foxi3-/- mice, we found that craniofacial dysmorphism was present. The results of comprehensive bioinformatics analysis suggested that the craniofacial dysmorphism caused by Foxi3 deficiency may be involved in the PI3K-Akt signaling pathway. Quantitative real-time PCR results showed that the expression of PI3K-Akt signaling pathway-related gene Akt2 was significantly increased in Foxi3-/- mice. CONCLUSION: The craniofacial dysmorphism caused by the deficiency of Foxi3 may be related to the expression of Akt2 and PI3K-Akt signaling pathway. This study laid a foundation for understanding the function of FOXI3 and the pathogenesis and treatment of related craniofacial dysmorphism caused by FOXI3 dysfunction.

Hao-Fountain syndrome: 32 novel patients reveal new insights into the clinical spectrum.

Hao-Fountain syndrome (HAFOUS, OMIM: #616863) is a neurodevelopmental disorder caused by pathogenic variants in the gene USP7 coding for USP7, a protein involved in several crucial cellular homeostatic mechanisms and the recently described MUST complex. The phenotype of HAFOUS is insufficiently understood, yet there is a great need to better understand the spectrum of disease, genotype-phenotype correlations, and disease trajectories. We now present a larger cohort of 32 additional individuals and provide further clinical information about six previously reported individuals. A questionnaire-based study was performed to characterize the phenotype of Hao-Fountain syndrome more clearly, to highlight new traits, and to better distinguish the disease from related neurodevelopmental disorders. In addition to confirming previously described features, we report hyperphagia and increased body weight in a subset of individuals. HAFOUS patients present an increased rate of birth complications, congenital anomalies, and abnormal pain thresholds. Speech impairment emerges as a potential hallmark of Hao-Fountain syndrome. Cognitive testing reports reveal borderline intellectual functioning on average, although some individuals score in the range of intellectual disability. Finally, we created a syndrome-specific severity score. This score neither indicates a sex- nor age-specific difference of clinical severity, yet highlights a more severe outcome when amino acid changes colocalize to the catalytic domain of the USP7 protein.

BTB domain mutations perturbing KCTD15 oligomerisation cause a distinctive frontonasal dysplasia syndrome.

INTRODUCTION: KCTD15 encodes an oligomeric BTB domain protein reported to inhibit neural crest formation through repression of Wnt/beta-catenin signalling, as well as transactivation by TFAP2. Heterozygous missense variants in the closely related paralogue KCTD1 cause scalp-ear-nipple syndrome. METHODS: Exome sequencing was performed on a two-generation family affected by a distinctive phenotype comprising a lipomatous frontonasal malformation, anosmia, cutis aplasia of the scalp and/or sparse hair, and congenital heart disease. Identification of a de novo missense substitution within KCTD15 led to targeted sequencing of DNA from a similarly affected sporadic patient, revealing a different missense mutation. Structural and biophysical analyses were performed to assess the effects of both amino acid substitutions on the KCTD15 protein. RESULTS: A heterozygous c.310G>C variant encoding p.(Asp104His) within the BTB domain of KCTD15 was identified in an affected father and daughter and segregated with the phenotype. In the sporadically affected patient, a de novo heterozygous c.263G>A variant encoding p.(Gly88Asp) was present in KCTD15. Both substitutions were found to perturb the pentameric assembly of the BTB domain. A crystal structure of the BTB domain variant p.(Gly88Asp) revealed a closed hexameric assembly, whereas biophysical analyses showed that the p.(Asp104His) substitution resulted in a monomeric BTB domain likely to be partially unfolded at physiological temperatures. CONCLUSION: BTB domain substitutions in KCTD1 and KCTD15 cause clinically overlapping phenotypes involving craniofacial abnormalities and cutis aplasia. The structural analyses demonstrate that missense substitutions act through a dominant negative mechanism by disrupting the higher order structure of the KCTD15 protein complex.

The landscape of SETBP1 gene expression and transcription factor activity across human tissues.

The SET binding protein 1 (SETBP1) gene encodes a transcription factor (TF) involved in various cellular processes. Variants in SETBP1 can result in three different diseases determined by the introduction (germline vs. somatic) and location of the variant. Germline variants cause the ultra-rare pediatric Schinzel Giedion Syndrome (SGS) and SETBP1 haploinsufficiency disorder (SETBP1-HD), characterized by severe multisystemic abnormalities with neurodegeneration or a less severe brain phenotype accompanied by hypotonia and strabismus, respectively. Somatic variants in SETBP1 are associated with hematological malignancies and cancer development in other tissues in adults. To better understand the tissue-specific mechanisms involving SETBP1, we analyzed publicly available RNA-sequencing (RNA-seq) data from the Genotype-Tissue Expression (GTEx) project. We found SETBP1 and its known target genes were widely expressed across 31 adult human tissues. K-means clustering identified three distinct expression patterns of SETBP1 targets across tissues. Functional enrichment analysis (FEA) of each cluster revealed gene sets related to transcriptional regulation, DNA binding, and mitochondrial function. TF activity analysis of SETBP1 and its target TFs revealed tissue-specific TF activity, underscoring the role of tissue context-driven regulation and suggesting its impact in SETBP1-associated disease. In addition to uncovering tissue-specific molecular signatures of SETBP1 expression and TF activity, we provide a Shiny web application to facilitate exploring TF activity across human tissues for 758 TFs. This study provides insight into the landscape of SETBP1 expression and TF activity across 31 non-diseased human tissues and reveals tissue-specific expression and activity of SETBP1 and its targets. In conjunction with the web application we constructed, our framework enables researchers to generate hypotheses related to the role tissue backgrounds play with respect to gene expression and TF activity in different disease contexts.

iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity.

PACS1 syndrome is a neurodevelopmental disorder characterized by intellectual disability and distinct craniofacial abnormalities resulting from a de novo p.R203W variant in phosphofurin acidic cluster sorting protein 1 (PACS1). PACS1 is known to have functions in the endosomal pathway and nucleus, but how the p.R203W variant affects developing neurons is not fully understood. Here we differentiated stem cells towards neuronal models including cortical organoids to investigate the impact of the PACS1 syndrome-causing variant on neurodevelopment. While few deleterious effects were detected in PACS1(+/R203W) neural precursors, mature PACS1(+/R203W) glutamatergic neurons exhibited impaired expression of genes involved in synaptic signaling processes. Subsequent characterization of neural activity using calcium imaging and multielectrode arrays revealed the p.R203W PACS1 variant leads to a prolonged neuronal network burst duration mediated by an increased interspike interval. These findings demonstrate the impact of the PACS1 p.R203W variant on developing human neural tissue and uncover putative electrophysiological underpinnings of disease.

Craniofacial anomalies in a murine model of heterozygous fibroblast growth factor 10 gene mutation.

OBJECTIVE: Dysregulation of Fibroblast Growth Factor 10 (FGF10), a member of the family of Fibroblast Growth Factor (FGF) proteins, has been implicated in craniofacial and dental anomalies, including craniosynostosis, cleft palate, and Lacrimo-Auriculo-Dento-Digital Syndrome. The aim of this murine study was to assess the craniofacial and dental phenotypes associated with a heterozygous FGF10 gene (FGF10+/- ) mutation at skeletal maturity. METHODS: Skulls of 40 skeletally mature mice, comprising two genotypes (heterozygous FGF10+/- mutation, n = 22; wildtype, n = 18) and two sexes (male, n = 23; female, n = 17), were subjected to micro-computed tomography. Landmark-based linear dimensions were measured for the cranial vault, maxilla, mandible, and first molar teeth. Multivariate analysis of variance was performed to assess whether there were significant differences in the craniofacial and dental structures between genotypes and sexes. RESULTS: The craniomaxillary skeleton and the first molar teeth were smaller in the FGF10+/- mice (P < .05), but the mandible was unaffected. Sex did not have a significant effect on these structures (P > .05). Cranial sutural defects were noted in 5/22 (22.7%) mutant versus 2/18 (11.1%) wildtype mice, and cleft palate in only one (4.5%) mutant mouse. None of the mice displayed craniosynostosis, expansive bony lesions, bifid condyles, or impacted teeth. CONCLUSION: The FGF10+/- mutation was associated with craniomaxillary skeletal hypoplasia that probably arose from deficient (delayed) intramembranous ossification of the sutured bones. Overall, the skeletal and dental data suggest that the FGF10 gene plays an important role in the aetiology of craniofacial dysmorphology and malocclusion.

Biallelic loss-of-function variants in CACHD1 cause a novel neurodevelopmental syndrome with facial dysmorphism and multisystem congenital abnormalities.

PURPOSE: We established the genetic etiology of a syndromic neurodevelopmental condition characterized by variable cognitive impairment, recognizable facial dysmorphism, and a constellation of extra-neurological manifestations. METHODS: We performed phenotypic characterization of 6 participants from 4 unrelated families presenting with a neurodevelopmental syndrome and used exome sequencing to investigate the underlying genetic cause. To probe relevance to the neurodevelopmental phenotype and craniofacial dysmorphism, we established two- and three-dimensional human stem cell-derived neural models and generated a stable cachd1 zebrafish mutant on a transgenic cartilage reporter line. RESULTS: Affected individuals showed mild cognitive impairment, dysmorphism featuring oculo-auriculo abnormalities, and developmental defects involving genitourinary and digestive tracts. Exome sequencing revealed biallelic putative loss-of-function variants in CACHD1 segregating with disease in all pedigrees. RNA sequencing in CACHD1-depleted neural progenitors revealed abnormal expression of genes with key roles in Wnt signaling, neurodevelopment, and organ morphogenesis. CACHD1 depletion in neural progenitors resulted in reduced percentages of post-mitotic neurons and enlargement of 3D neurospheres. Homozygous cachd1 mutant larvae showed mandibular patterning defects mimicking human facial dysmorphism. CONCLUSION: Our findings support the role of loss-of-function variants in CACHD1 as the cause of a rare neurodevelopmental syndrome with facial dysmorphism and multisystem abnormalities.

Exploring the roles of noncoding RNAs in craniofacial abnormalities: A systematic review.

Congenital craniofacial abnormalities are congenital anomalies of variable expressivity and severity with a recognizable set of abnormalities, which are derived from five identifiable primordial structures. They can occur unilaterally or bilaterally and include various malformations such as cleft lip with/without palate, craniosynostosis, and craniofacial microsomia. To date, the molecular etiology of craniofacial abnormalities is largely unknown. Noncoding RNAs (ncRNAs), including microRNAs, long ncRNAs, circular RNAs and PIWI-interacting RNAs, function as major regulators of cellular epigenetic hallmarks via regulation of various molecular and cellular processes. Recently, aberrant expression of ncRNAs has been implicated in many diseases, including craniofacial abnormalities. Consequently, this review focuses on the role and mechanism of ncRNAs in regulating craniofacial development in the hope of providing clues to identify potential therapeutic targets.

[Analysis of genetic variants in a child with Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism without seizures].

OBJECTIVE: To explore the clinical phenotype and genetic characteristics of a child with Intellectual developmental disorder with behavioral abnormalities and craniofacial malformations without epilepsy (IDDBCS). METHODS: A child who had visited the Lianyungang Maternal and Child Health Care Hospital in April 2021 was selected as the study subject. Clinical data of the child were collected. Genomic DNA was extracted from peripheral blood samples of the child and his parents and subjected to whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing of his family members. RESULTS: The child, a 3-year-and-4-month-old male, had presented with global developmental delay and cranial malformation. Genetic testing revealed that he has harbored a heterozygous c.1703delA (p.K568Sfs9) variant of the PHF21A gene, for which both of his parents were of the wild type. This low-frequency variant may alter the structure and function of the protein product. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), it was classified as a pathogenic variant (PVS1+PS2+PM2_Supporting). CONCLUSION: The heterozygous c.1703delA (p.K568Sfs9) variant of the PHF21A gene probably underlay the IDDBCS in this patient.

SETting up the genome: KMT2D and KDM6A genomic function in the Kabuki syndrome craniofacial developmental disorder.

BACKGROUND: Kabuki syndrome is a congenital developmental disorder that is characterized by distinctive facial gestalt and skeletal abnormalities. Although rare, the disorder shares clinical features with several related craniofacial syndromes that manifest from mutations in chromatin-modifying enzymes. Collectively, these clinical studies underscore the crucial, concerted functions of chromatin factors in shaping developmental genome structure and driving cellular transcriptional states. Kabuki syndrome predominantly results from mutations in KMT2D, a histone H3 lysine 4 methylase, or KDM6A, a histone H3 lysine 27 demethylase. AIMS: In this review, we summarize the research efforts to model Kabuki syndrome in vivo to understand the cellular and molecular mechanisms that lead to the craniofacial and skeletal pathogenesis that defines the disorder. DISCUSSION: As several studies have indicated the importance of KMT2D and KDM6A function through catalytic-independent mechanisms, we highlight noncanonical roles for these enzymes as recruitment centers for alternative chromatin and transcriptional machinery.

Deletion of taf1 and taf5 in zebrafish capitulate cardiac and craniofacial abnormalities associated with TAFopathies through perturbations in metabolism.

Intellectual disability is a neurodevelopmental disorder that affects 2-3% of the general population. Syndromic forms of intellectual disability frequently have a genetic basis and are often accompanied by additional developmental anomalies. Pathogenic variants in components of TATA-binding protein associated factors (TAFs) have recently been identified in a subset of patients with intellectual disability, craniofacial hypoplasia, and congenital heart disease. This syndrome has been termed as a TAFopathy and includes mutations in TATA binding protein (TBP), TAF1, TAF2, and TAF6. The underlying mechanism by which TAFopathies give rise to neurodevelopmental, craniofacial, and cardiac abnormalities remains to be defined. Through a forward genetic screen in zebrafish, we have recovered a recessive mutant phenotype characterized by craniofacial hypoplasia, ventricular hypoplasia, heart failure at 96 h post-fertilization and lethality, and show it is caused by a nonsense mutation in taf5. CRISPR/CAS9 mediated gene editing revealed that these defects where phenocopied by mutations in taf1 and taf5. Mechanistically, taf5-/- zebrafish displayed misregulation in metabolic gene expression and metabolism as evidenced by RNA sequencing, respiration assays, and metabolite studies. Collectively, these findings suggest that the TAF complex may contribute to neurologic, craniofacial, and cardiac development through regulation of metabolism.

Dominant frontonasal dysplasia with ectodermal defects results from increased activity of ALX4.

Frontonasal dysplasia (FND) refers to a group of rare developmental disorders characterized by abnormal morphology of the craniofacial region. We studied a family manifesting with clinical features typical for FND2 including neurobehavioral abnormalities, hypotrichosis, hypodontia, and facial dysmorphism. Whole-exome sequencing analysis identified a novel heterozygous frameshift insertion in ALX4 (c.985_986insGTGC, p.Pro329Argfs*115), encoding aristaless homeobox 4. This and a previously reported dominant FND2-causing variant are predicted to result in the formation of a similar abnormally elongated protein tail domain. Using a reporter assay, we showed that the elongated ALX4 displays increased activity. ALX4 negatively regulates the Wnt/ß-catenin pathway and accordingly, patient keratinocytes showed altered expression of genes associated with the WNT/ß-catenin pathway, which in turn may underlie ectodermal manifestations in FND2. In conclusion, dominant FND2 with ectodermal dysplasia results from frameshift variants in ALX4 exerting a gain-of-function effect.

[A case of intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures caused by PHF21A gene variation and review of literature].

Objective: To discuss the clinical and genetic features of intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures (IDDBCS). Methods: The clinical and genetic records of a patient who was diagnosed with IDDBCS caused by PHF21A gene variation at Children's Hospital Capital Institute of Pediatrics in 2021 were collected retrospectively. Using " PHF21A gene" as the keyword, relevant articles were searched at CNKI, Wanfang Data and PubMed from establishment of databases to February 2023. Clinical and genetic features of IDDBCS were summarized in the combination of this case. Results: An 8 months of age boy showed overgrowth (height, weight and head circumference were all higher than the 97th percentile of children of the same age and sex) and language and motor developmental delay after birth, and gradually showed autism-like symptoms like stereotyped behavior and poor eye contact. At 8 months of age, he began to show epileptic seizures, which were in the form of a series of spastic seizures with no reaction to adrenocorticotropic hormone but a good response to vigabatrin. Physical examination showed special craniofacial appearances including a prominent high forehead, sparse eyebrows, broad nasal bridge, and downturned mouth with a tent-shaped upper lip. The patient also manifested hypotonia. Whole exome sequencing showed a de novo heterogeneous variant, PHF21A (NM_001101802.1): c.54+1G>A, and IDDBCS was diagnosed. A total of 6 articles (all English articles) were collected, involving this case and other 14 patients of IDDBCS caused by PHF21A gene variation. Clinical manifestations were intellectual disability or developmental delay (15 patients), craniofacial anomalies (15 patients), behavioral abnormalities (12 patients), seizures (9 patients), and overgrowth (8 patients). The main pathogenic variations were frameshift variations (8 patients). Conclusions: IDDBCS should be considered when patients show nervous developmental abnormalities, craniofacial anomalies, seizures and overgrowth. PHF21A gene variation detection helps to make a definite diagnosis.

[Regulatory role and mechanism of primary cilia in craniofacial and dental development].

Primary cilia protruding from cell surface are important cell receptors and exist in most types of vertebrate cells. Primary cilia can sense extracellular mechanical signals, chemical signals as well as optical signals, and transduce them into cells, which is crucial for embryonic development and maintenance of tissue homeostasis. Mutations of gene that are responsible for the structure or function of cilia can lead to abnormal cilia signal transport, which in turn leads to ciliopathies. About 30% of ciliopathies are characterized by craniofacial phenotype. The most common cilia-related craniofacial defects include micrognathia, cleft lip, cleft palate, orbital hypertelorism/hypotelorism, flat nasal bridge, prominent forehead, craniosynostosis, and so on, suggesting that primary cilia plays an important role in the normal development of craniofacial development. This review summarizes the key genes involved in the regulation of craniofacial development in primary cilia and the disease phenotypes caused by important cilia gene mutations, in order to provide a reference for understanding the etiology of primary cilia-related craniofacial congenital developmental defects.

The Impact of Genetic Variability of TGF-Beta Signaling Biomarkers in Major Craniofacial Syndromes.

Craniofacial development is a complex process involving several signaling pathways, including the one regulated by the TGF-beta (TGF-ß) superfamily of growth factors. Isoforms of TGF-ß play a vital part in embryonic development, notably in craniofacial patterning. Consequently, pathogenic variants in their coding genes may result in a variety of orofacial and craniofacial malformations. Here, we review the impact of genetic variability of TGF-ß signaling biomarkers in major disorders, including palatal and lip clefts, dental anomalies, and craniofacial syndromes, such as the Loeys-Dietz syndrome (LDS) and Camurati-Engelmann disease. Cleft lip and cleft palate are associated with missense mutations in the TGFB1 and TGFB3 genes, while mutations in the LTBP3 gene encoding TGF-ß binding protein 3 may cause selective tooth agenesis. Oligodontia may also be caused by TGFB1-inactivating mutations and/or by variations in the GREM2 gene, which disrupt the activity of gremlin 2, a TGF-ß/bone morphogenetic protein (BMP4) signaling antagonist. CED may be caused by mutations in the TGFB1 gene, while the TGF-ß-related genetic background of LDS consists mostly of TGFBR1 and TGFBR2 mutations, which may also impact the above syndromes' vascular manifestations. The potential utility of the TGF-ß signaling pathway factors as biomarkers that correlate genetics with clinical outcome of craniofacial malformations is discussed.

The impact of SETBP1 mutations in neurological diseases and cancer.

SE translocation (SET) is a cancer-promoting factor whose expression is upregulated in many cancers. High SET expression positively correlates with a poor cancer prognosis. SETBP1 (SET-binding protein 1/SEB/MRD29), identified as SET-binding protein, is the causative gene of Schinzel-Giedion syndrome, which is characterized by severe intellectual disability and a distorted facial appearance. Mutations in these genetic regions are also observed in some blood cancers, such as myelodysplastic syndromes, and are associated with a poor prognosis. However, the physiological role of SETBP1 and the molecular mechanisms by which the mutations lead to disease progression have not yet been fully elucidated. In this review, we will describe the current epidemiological data on SETBP1 mutations and shed light on the current knowledge about the SET-dependent and -independent functions of SETBP1.

Long-term follow-up and novel variant in Suleiman-El-Hattab syndrome: Expanding the genotypic and clinical spectrum of a rare neurodevelopmental disorder.

Suleiman-El-Hattab syndrome (SULEHS, OMIM #618950) is an autosomal recessive multisystem developmental disorder characterized by distinctive facial appearance, global developmental delay/intellectual disability, poor expressive speech and happy demeanor. SULEHS is an ultra-rare disorder associated with biallelic loss-of-function variants of the TASP1 gene, and up-to-date, seven patients from five families have been reported in the literature. Loss of TASP1 function has been reported to alter H3K4 histone modifications and expression of TFIIA and HOX transcription factors in the SULEHS phenotype. In this report, a new patient molecularly diagnosed with SULEHS by a novel homozygous c.404-2A > G variant in the TASP1 gene is presented with the long-term follow-up. Although the majority of the patient's clinical characteristics were similar to those of previously reported SULEHS patients, this study was the first to describe some additional anomalies, such as cystic hygroma, increased nuchal thickness, coarctation of the aorta, pulmonary stenosis, pulmonary sequestration anomaly, chronic constipation, encephalomalacia, and aggressive behavior. Because of the remarkable similarities between the clinical features of Baraitser-Winter syndrome (BRWS) and the patient, BRWS was considered the most likely diagnosis before the molecular diagnosis. Network analysis also supported that the interaction of the SULEHS-associated TASP1 gene with the BRWS-associated ACTB and ACTG1 genes through common intermediate molecules. Overall, despite the existence of differences in clinical features, inheritance patterns, and underlying pathophysiology between BRWS and SULEHS, both diseases could be considered in the differential diagnosis due to the high clinical similarities, including the dysmorphic features, growth parameters, neurodevelopmental phenotype, neurological problems, and multisystem involvement. Additionally, this report could contribute to a better understanding of the genotypic and clinical features of SULEHS by describing a novel pathogenic variant and new clinical features, such as prenatal manifestations.

Dominant negative variants in IKZF2 cause ICHAD syndrome, a new disorder characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay.

BACKGROUND: Helios (encoded by IKZF2), a member of the Ikaros family of transcription factors, is a zinc finger protein involved in embryogenesis and immune function. Although predominantly recognised for its role in the development and function of T lymphocytes, particularly the CD4+ regulatory T cells (Tregs), the expression and function of Helios extends beyond the immune system. During embryogenesis, Helios is expressed in a wide range of tissues, making genetic variants that disrupt the function of Helios strong candidates for causing widespread immune-related and developmental abnormalities in humans. METHODS: We performed detailed phenotypic, genomic and functional investigations on two unrelated individuals with a phenotype of immune dysregulation combined with syndromic features including craniofacial differences, sensorineural hearing loss and congenital abnormalities. RESULTS: Genome sequencing revealed de novo heterozygous variants that alter the critical DNA-binding zinc fingers (ZFs) of Helios. Proband 1 had a tandem duplication of ZFs 2 and 3 in the DNA-binding domain of Helios (p.Gly136_Ser191dup) and Proband 2 had a missense variant impacting one of the key residues for specific base recognition and DNA interaction in ZF2 of Helios (p.Gly153Arg). Functional studies confirmed that both these variant proteins are expressed and that they interfere with the ability of the wild-type Helios protein to perform its canonical function-repressing IL2 transcription activity-in a dominant negative manner. CONCLUSION: This study is the first to describe dominant negative IKZF2 variants. These variants cause a novel genetic syndrome characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay.

Displasia frontonasal / Frontonasal dysplasia

Los trastornos del desarrollo son aquellos padecimientos que se manifiestan por defectos en la embriogénesis de la región afectada. La cara del ser humano comienza su formación alrededor de la cuarta semana de vida intrauterina y se manifiesta gracias a la fusión de cinco prominencias: dos pares conocidas como maxilar y mandibular, y una impar conocida como frontonasal. Cuando esta fusión no se lleva a cabo de una forma óptima, aparecen numerosas alteraciones del desarrollo como el labio y paladar hendido, y la displasia frontonasal. La displasia frontonasal produce frecuentemente afecciones oculares, nasales y orales. Dentro de las manifestaciones orales destacan una forma atípica de hendidura labial o palatina, afecciones dentales y alteraciones en el crecimiento de la cara. Dada la gran relación que este padecimiento tiene con la cavidad oral resulta importante que el odontólogo conozca la etiología y las características clínicas de este trastorno (AU)

Developmental disorders are those conditions that are manifested by defects in the embryogenesis of the affected region. The human face begins its formation around the fourth week of intrauterine life and is manifested thanks to the fusion of five prominences: two pairs known as maxillary and mandibular and odd one known as frontonasal. When this fusion is not carried out in an optimal way, numerous developmental alterations appear, such as cleft lip and palate and frontonasal dysplasia. Frontonasal dysplasia frequently produces ocular, nasal and oral affections. Among the oral manifestations, and atypical form of clef lip and/or palate, dental affections and alterations in the growth of the face stand out. Given the great relationship that this condition has with the oral cavity, it is important for the dentist to know the etiology and clinical characteristics of this disorder (AU)