Human Genetics of Ventricular Septal Defect.

Ventricular septal defects (VSDs) are recognized as one of the commonest congenital heart diseases (CHD), accounting for up to 40% of all cardiac malformations, and occur as isolated CHDs as well as together with other cardiac and extracardiac congenital malformations in individual patients and families. The genetic etiology of VSD is complex and extraordinarily heterogeneous. Chromosomal abnormalities such as aneuploidy and structural variations as well as rare point mutations in various genes have been reported to be associated with this cardiac defect. This includes both well-defined syndromes with known genetic cause (e.g., DiGeorge syndrome and Holt-Oram syndrome) and so far undefined syndromic forms characterized by unspecific symptoms. Mutations in genes encoding cardiac transcription factors (e.g., NKX2-5 and GATA4) and signaling molecules (e.g., CFC1) have been most frequently found in VSD cases. Moreover, new high-resolution methods such as comparative genomic hybridization enabled the discovery of a high number of different copy number variations, leading to gain or loss of chromosomal regions often containing multiple genes, in patients with VSD. In this chapter, we will describe the broad genetic heterogeneity observed in VSD patients considering recent advances in this field.

Human Genetics of Semilunar Valve and Aortic Arch Anomalies.

Lesions of the semilunar valve and the aortic arch can occur either in isolation or as part of well-described clinical syndromes. The polygenic cause of calcific aortic valve disease will be discussed including the key role of NOTCH1 mutations. In addition, the complex trait of bicuspid aortic valve disease will be outlined, both in sporadic/familial cases and in the context of associated syndromes, such as Alagille, Williams, and Kabuki syndromes. Aortic arch abnormalities particularly coarctation of the aorta and interrupted aortic arch, including their association with syndromes such as Turner and 22q11 deletion, respectively, are also discussed. Finally, the genetic basis of congenital pulmonary valve stenosis is summarized, with particular note to Ras-/mitogen-activated protein kinase (Ras/MAPK) pathway syndromes and other less common associations, such as Holt-Oram syndrome.

Fetal Phenotype of CHARGE Syndrome with a Molecular Confirmation: A Series of 13 Cases.

INTRODUCTION: CHARGE syndrome is an autosomal dominant genetic disorder with known pattern of features. The aim of the study was to present the fetal features of CHARGE syndrome to gain awareness that the antenatal characteristics can be very nonspecific. CASE PRESENTATION: This was a retrospective study of 13 cases with CHARGE syndrome diagnosed by prenatal or postnatal genetic testing and physical examination. Two (15.4%; 2/13) had normal ultrasound scans during pregnancy. One (7.7%; 1/13) with first-trimester cystic hygroma presented intrauterine fetal demise at 16 weeks gestation. The remaining 10 (76.9%; 10/13) cases had abnormal ultrasound features in utero; among these, 1 had an increased nuchal translucency in the first trimester, 5 had second-trimester abnormal ultrasounds including micrognathia, cardiac defects, and facial defects, and 4 third-trimester abnormal ultrasounds including micrognathia, isolated fetal growth restriction, and polyhydramnios. Among the 11 cases with abnormal prenatal ultrasound scans, no fetus could reach the diagnostic criteria of CHARGE syndrome if only based on the results of ultrasound. However, the diagnosis was made in all cases when CHD7 defects were detected. DISCUSSION/CONCLUSION: The CHARGE syndrome presents non-specific abnormal ultrasound markers in utero. Exome sequencing in the genetic workup will aid in prenatal diagnosis of this syndrome.

Combined pituitary hormone deficiency harboring CHD7 gene missense mutation without CHARGE syndrome: a case report.

BACKGROUND: Heterozygous loss-of-function mutations in the chromodomain helicase DNA-binding protein 7 (CHD7) gene cause CHARGE syndrome characterized by various congenital anomalies. A majority of patients with CHARGE syndrome present with congenital hypogonadotropic hypogonadism (HH), and combined pituitary hormone deficiency (CPHD) can also be present. Whereas CHD7 mutations have been identified in some patients with isolated HH without a diagnosis of CHARGE syndrome, it remains unclear whether CHD7 mutations can be identified in patients with CPHD who do not fulfill the criteria for CHARGE syndrome. CASE PRESENTATION: A 33-year-old woman was admitted to our hospital. She had primary amenorrhea and was at Tanner stage 2 for both pubic hair and breast development. She was diagnosed with CPHD (HH, growth hormone deficiency, and central hypothyroidism), and a heterozygous rare missense mutation (c.6745G > A, p.Asp2249Asn) in the CHD7 gene was identified. Our conservation analysis and numerous in silico analyses suggested that this mutation had pathogenic potential. She had mild intellectual disability, a minor feature of CHARGE syndrome, but did not fulfill the criteria for CHARGE syndrome. CONCLUSIONS: We report a rare case of CPHD harboring CHD7 mutation without CHARGE syndrome. This case provides valuable insights into phenotypes caused by CHD7 mutations. CHD7 mutations can have a continuous phenotypic spectrum depending on the severity of hypopituitarism and CHARGE features. Therefore, we would like to propose a novel concept of CHD7-associated syndrome.

Expanding the reproductive organ phenotype of CHD7-spectrum disorder.

CHD7 disorder is a multiple congenital anomaly syndrome with a highly variable phenotypic spectrum, and includes CHARGE syndrome. Internal and external genital phenotypes frequently seen in CHD7 disorder include cryptorchidism and micropenis in males, and vaginal hypoplasia in females, both thought to be secondary to hypogonadotropic hypogonadism. Here, we report 14 deeply phenotyped individuals with known CHD7 variants (9 pathogenic/likely pathogenic and 5 VOUS) and a range of reproductive and endocrine phenotypes. Reproductive organ anomalies were observed in 8 of 14 individuals and were more commonly noted in males (7/7), most of whom presented with micropenis and/or cryptorchidism. Kallmann syndrome was commonly observed among adolescents and adults with CHD7 variants. Remarkably, one 46,XY individual presented with ambiguous genitalia, cryptorchidism with Müllerian structures including uterus, vagina and fallopian tubes, and one 46,XX female patient presented with absent vagina, uterus and ovaries. These cases expand the genital and reproductive phenotype of CHD7 disorder to include two individuals with genital/gonadal atypia (ambiguous genitalia), and one with Müllerian aplasia.

Acute myeloid leukemia associated with CHARGE syndrome.

CHARGE syndrome is a malformation disorder with diverse phenotypes that shows autosomal dominance with heterozygous variants in the chromodomain helicase DNA-binding 7 (CHD7) gene. Only a few cases of CHARGE syndrome accompanied by neoplasm during childhood have been reported. We report the case of a girl with CHARGE syndrome who developed acute myelogenous leukemia at 12 years old. She had mild intellectual disability, and hearing loss with inner ear malformation, myopia, astigmatism, laryngotracheal malacia, hypogonadism, and clival hypoplasia, with a history of patent ductus arteriosus. The patient was genetically diagnosed with CHARGE syndrome based on the detection of a novel heterozygous frameshift pathogenic variant in the CHD7 gene. We review the reported pediatric cases of CHARGE syndrome with malignancy and suggest a possible molecular mechanism of carcinogenesis involving pathogenic variants of the CHD7 gene.

The CHARGE syndrome ortholog CHD-7 regulates TGF-ß pathways in Caenorhabditis elegans.

CHARGE syndrome is a complex developmental disorder caused by mutations in the chromodomain helicase DNA-binding protein-7 (CHD7) and characterized by retarded growth and malformations in the heart and nervous system. Despite the public health relevance of this disorder, relevant cellular pathways and targets of CHD7 that relate to disease pathology are still poorly understood. Here we report that chd-7, the nematode ortholog of Chd7, is required for dauer morphogenesis, lifespan determination, stress response, and body size determination. Consistent with our discoveries, we found chd-7 to be allelic to scd-3, a previously identified dauer suppressor from the DAF-7/ tumor growth factor-ß (TGF-ß) pathway. Epistatic analysis places CHD-7 at the level of the DAF-3/DAF-5 complex, but we found that CHD-7 also directly impacts the expression of multiple components of this pathway. Transcriptomic analysis revealed that chd-7 mutants fail to repress daf-9 for execution of the dauer program. In addition, CHD-7 regulates the DBL-1/BMP pathway components and shares roles in male tail development and cuticle synthesis. To explore a potential conserved function for chd-7 in vertebrates, we used Xenopus laevis embryos, an established model to study craniofacial development. Morpholino-mediated knockdown of Chd7 led to a reduction in col2a1 messenger RNA (mRNA) levels, a collagen whose expression depends on TGF-ß signaling. Both embryonic lethality and craniofacial defects in Chd7-depleted tadpoles were partially rescued by overexpression of col2a1 mRNA. We suggest that Chd7 has conserved roles in regulation of the TGF-ß signaling pathway and pathogenic Chd7 could lead to a defective extracellular matrix deposition.

Combination of BMI1 and MAPK/ERK inhibitors is effective in medulloblastoma.

BACKGROUND: Epigenetic changes play a key role in the pathogenesis of medulloblastoma (MB), the most common malignant pediatric brain tumor. METHODS: We explore the therapeutic potential of BMI1 and MAPK/ERK inhibition in BMI1High;CHD7Low MB cells and in a preclinical xenograft model. RESULTS: We identify a synergistic vulnerability of BMI1High;CHD7Low MB cells to a combination treatment with BMI1 and MAPK/ERK inhibitors. Mechanistically, CHD7-dependent binding of BMI1 to MAPK-regulated genes underpins the CHD7-BMI1-MAPK regulatory axis responsible of the antitumour effect of the inhibitors in vitro and in a preclinical mouse model. Increased ERK1 and ERK2 phosphorylation activity is found in BMI1High;CHD7Low G4 MB patients, raising the possibility that they could be amenable to a similar therapy. CONCLUSIONS: The molecular dissection of the CHD7-BMI1-MAPK regulatory axis in BMI1High;CHD7Low MB identifies this signature as a proxy to predict MAPK functional activation, which can be effectively drugged in preclinical models, and paves the way for further exploration of combined BMI1 and MAPK targeting in G4 MB patients.

De novo Splice Site Mutation of the CHD7 Gene in a Chinese Patient with Typical CHARGE Syndrome.

INTRODUCTION: CHARGE syndrome (CS, OMIM 214800) is a rare genetic disease characterized by multiple congenital abnormalities, including coloboma, heart defect, atresia of the choanae, retardation of development, genital anomalies, and ear anomalies/deafness. The syndrome is mainly caused by a heterozygous variant in the chromodomain helicase DNA-binding protein 7 (CHD7) gene that encodes the CHD7 protein, involved in the ATP-dependent remodeling of chromatin. METHODS: In this study, the next-generation sequencing targeted panel was used to detect a de novo variant c.3523-2A>G in the CHD7 gene in a patient with severe CS, congenital heart disease, left coloboma of the choroid, cryptorchidism, and congenital deafness. The Sanger sequencing confirmed the variant and clarified it as de novo variant by short tandem repeat analysis in the patient family. We analyzed the effect of a variant by Minigene assay to evaluate the pathogenicity of the variant. RESULTS: In summary, cDNA analysis confirmed that c.3523-2A>G variant activates a cryptic splice site, resulting in 172 base pair missing in exon 15, leading to the premature truncation of the CHD7 protein (p.V1175Afs*11). CONCLUSION: The present study functionally characterized the novel c.3523-2A>G variant in CHD7, providing further confirmatory evidence that it is associated with CS.

A novel heterozygous mutation of CHD7 gene in a Chinese patient with Kallmann syndrome: a case report.

BACKGROUND: Variants of chromodomain helicase DNA binding protein 7 (CHD7) gene are commonly associated with Kallmann syndrome (KS) and account for 5-6% of idiopathic hypogonadotropic hypogonadism (IHH) cases. Here we report a novel mutation of CHD7 gene in a patient with KS, which may contribute to the better understanding of KS. CASE PRESENTATION: A 29-year-old male patient with KS and a chief complaint of delayed puberty for 13 years (Tanner B Stage< 4) was admitted to the Department of Endocrinology of the First Affiliated Hospital of Zhejiang University (Hangzhou, China) in September 2019. Dual-energy X-ray absorptiometry (DEXA) showed low bone density in both lumbar spine (L1 ~ L5 mean Z-score - 3.0) and femoral neck (Z-score - 2.7). Dynamic contrast-enhanced magnetic resonance imaging (MRI) of pituitary and contrast-enhanced computed tomography (CT) showed no abnormal findings. Ophthalmological evaluation showed that his both eyes showed exotropia, and no sight loss was noted. Heterozygous c.1619G > T mutation of TCD7 gene (p.G4856V) was detected, whereas none of his family members had this mutation. Human chorionic gonadotropin (HCG) and human menopausal gonadotropin (HMG) were injected for three times/week to treat idiopathic hypogonadotropic hypogonadism (IHH). After several months of therapy, the patient's health condition improved. His testicles became larger, and his secondary sexual characteristics improved after treatment. CONCLUSION: Exploration of the novel splice-site mutation of CHD7 may further our current understanding of KS.

Visual Function and Ophthalmological Findings in CHARGE Syndrome: Revision of Literature, Definition of a New Clinical Spectrum and Genotype Phenotype Correlation.

CHARGE syndrome (CS) is a rare genetic disease causing multiple anatomical defects and sensory impairment. Visual function is usually reported by caregivers and has never been described with a structured behavioral assessment. Our primary objective was to describe ocular abnormalities, visual function and genotype-ocular-phenotype correlation in CS. A prospective monocentric cohort study was performed on 14 children with CS carrying pathogenic CHD7 variants. All children underwent ophthalmological evaluation and structured behavioral assessment of visual function. The VISIOCHARGE questionnaire was administered to parents. Colobomas were present in 93% of patients. Genotype-phenotype correlation documented mitigated features in a subset of patients with intronic pathogenic variants predicted to affect transcript processing, and severe features in patients with frameshift/nonsense variants predicting protein truncation at the N-terminus. Abnormal visual function was present in all subjects, with different degrees of impairment. A significant correlation was found between visual function and age at assessment (p-value = 0.025). The present data are the first to characterize visual function in CS patients. They suggest that hypomorphic variants might be associated with milder features, and that visual function appears to be related to age. While studies with larger cohorts are required for confirmation, our data indicate that experience appears to influence everyday use of visual function more than ocular abnormalities do.

Semaphorin Regulation by the Chromatin Remodeler CHD7: An Emerging Genetic Interaction Shaping Neural Cells and Neural Crest in Development and Cancer.

CHD7 is a chromatin remodeler protein that controls gene expression via the formation of multi-protein complexes with specific transcription factors. During development, CHD7 controls several differentiation programs, mainly by acting on neural progenitors and neural crest (NC) cells. Thus, its roles range from the central nervous system to the peripheral nervous system and the organs colonized by NC cells, including the heart. Accordingly, mutated CHD7 is linked to CHARGE syndrome, which is characterized by several neuronal dysfunctions and by malformations of NC-derived/populated organs. Altered CHD7 has also been associated with different neoplastic transformations. Interestingly, recent evidence revealed that semaphorins, a class of molecules involved in developmental and pathological processes similar to those controlled by CHD7, are regulated by CHD7 in a context-specific manner. In this article, we will review the recent insights that support the existence of genetic interactions between these pathways, both during developmental processes and cancer progression.

CHD7 regulates cardiovascular development through ATP-dependent and -independent activities.

CHD7 encodes an ATP-dependent chromatin remodeling factor. Mutation of this gene causes multiple developmental disorders, including CHARGE (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth/development, Genital abnormalities, and Ear anomalies) syndrome, in which conotruncal anomalies are the most prevalent form of heart defects. How CHD7 regulates conotruncal development remains unclear. In this study, we establish that deletion of Chd7 in neural crest cells (NCCs) causes severe conotruncal defects and perinatal lethality, thus providing mouse genetic evidence demonstrating that CHD7 cell-autonomously regulates cardiac NCC development, thereby clarifying a long-standing controversy in the literature. Using transcriptomic analyses, we show that CHD7 fine-tunes the expression of a gene network that is critical for cardiac NCC development. To gain further molecular insights into gene regulation by CHD7, we performed a protein-protein interaction screen by incubating recombinant CHD7 on a protein array. We find that CHD7 directly interacts with several developmental disorder-mutated proteins including WDR5, a core component of H3K4 methyltransferase complexes. This direct interaction suggested that CHD7 may recruit histone-modifying enzymes to target loci independently of its remodeling functions. We therefore generated a mouse model that harbors an ATPase-deficient allele and demonstrates that mutant CHD7 retains the ability to recruit H3K4 methyltransferase activity to its targets. Thus, our data uncover that CHD7 regulates cardiovascular development through ATP-dependent and -independent activities, shedding light on the etiology of CHD7-related congenital disorders. Importantly, our data also imply that patients carrying a premature stop codon versus missense mutations will likely display different molecular alterations; these patients might therefore require personalized therapeutic interventions.

T-Cell Immunodeficiencies With Congenital Alterations of Thymic Development: Genes Implicated and Differential Immunological and Clinical Features.

Combined Immunodeficiencies (CID) are rare congenital disorders characterized by defective T-cell development that may be associated with B- and NK-cell deficiency. They are usually due to alterations in genes expressed in hematopoietic precursors but in few cases, they are caused by impaired thymic development. Athymia was classically associated with DiGeorge Syndrome due to TBX1 gene haploinsufficiency. Other genes, implicated in thymic organogenesis include FOXN1, associated with Nude SCID syndrome, PAX1, associated with Otofaciocervical Syndrome type 2, and CHD7, one of the genes implicated in CHARGE syndrome. More recently, chromosome 2p11.2 microdeletion, causing FOXI3 haploinsufficiency, has been identified in 5 families with impaired thymus development. In this review, we will summarize the main genetic, clinical, and immunological features related to the abovementioned gene mutations. We will also focus on different therapeutic approaches to treat SCID in these patients.

CHD7 and Runx1 interaction provides a braking mechanism for hematopoietic differentiation.

Hematopoietic stem and progenitor cell (HSPC) formation and lineage differentiation involve gene expression programs orchestrated by transcription factors and epigenetic regulators. Genetic disruption of the chromatin remodeler chromodomain-helicase-DNA-binding protein 7 (CHD7) expanded phenotypic HSPCs, erythroid, and myeloid lineages in zebrafish and mouse embryos. CHD7 acts to suppress hematopoietic differentiation. Binding motifs for RUNX and other hematopoietic transcription factors are enriched at sites occupied by CHD7, and decreased RUNX1 occupancy correlated with loss of CHD7 localization. CHD7 physically interacts with RUNX1 and suppresses RUNX1-induced expansion of HSPCs during development through modulation of RUNX1 activity. Consequently, the RUNX1:CHD7 axis provides proper timing and function of HSPCs as they emerge during hematopoietic development or mature in adults, representing a distinct and evolutionarily conserved control mechanism to ensure accurate hematopoietic lineage differentiation.

CHARGE syndrome without colobomas: Ophthalmic findings.

To report ophthalmic findings of patients without colobomas, and with a clinical and molecular diagnosis of CHARGE Syndrome. Retrospective study of ophthalmic findings in 67 CHARGE patients-clinically confirmed diagnosis with positive CHD7 mutation-seen in the Ophthalmology department of Cincinnati Children's Hospital Medical Center between January 1, 2008 through September 25, 2018. Criteria for inclusion in this study was absence of any form of a coloboma in either eye. In our cohort, all patients had a positive CHD7 mutation, in addition to a clinical diagnosis. 19.4% (13/67) of CHARGE patients did not have a coloboma in either eye. 69.2% (9/13) had strabismus, 76.9% (10/13) had a refractive error that warranted refractive correction, 23.1% (3/13) had amblyopia, 38.5% (5/13) had nasolacrimal duct obstruction, 30.8% (4/13) had dry eye syndrome and exposure keratopathy, 15.4% (2/13) had ptosis, 15.4% (2/13) had blepharitis, 15.4% (2/13) had Cortical Visual Impairment, 7.7% (1/13) of patients had optic nerve drusen, 7.7% (1/13) had Marcus Gunn Jaw Winking, and 7.7% (1/13) with an eyelid nevus. There are numerous ophthalmic findings in individuals with CHARGE Syndrome without colobomas. No study to date has evaluated the ophthalmic findings in CHD7 positive CHARGE patients without colobomas. These findings need to be assessed and treated to ensure optimal vision in the CHARGE patient population. Absence of coloboma does not rule out a diagnosis of CHARGE syndrome, and if there is a clinical suspicion, clinical confirmation then genetic testing would be warranted.

SEMA3A and IGSF10 Are Novel Contributors to Combined Pituitary Hormone Deficiency (CPHD).

Background: The mutation frequencies of pituitary transcription factors genes in patients with combined pituitary hormone deficiencies (CPHD) vary substantially between populations. However, apart from PROP1 the mutation rate of other genes is low and for almost half of the patients with CPHD the routine sequencing of known genes is unsuccessful in the identification of genetic causes. Methods: A cohort of 66 sporadic and nine familial CPHD cases (80 patients in total) were subjected to initial testing of the genes PROP1, POU1F1, LHX3, LHX4, and HESX1 using a targeted gene panel and MLPA. In patients who tested negative, a whole exome sequencing approach was employed. Results: In nine of the familial cases and 32 of the sporadic patients mutations in the PROP1 gene were found (the common pathogenic variants included c.301_302delAG and c.150delA). Mutations were also found in genes so far not related directly to CPHD. A unique homozygous and clinically relevant variant was identified in the SEMA3A gene, which may contribute to neural development and his phenotypic spectrum including short stature and isolated hypogonadotropic hypogonadism (IHH). Another pathogenic variant p.A1672T was found in the IGSF10 gene reported to be responsible for delayed puberty and neuronal migration during embryogenesis. Several suspected novel but predicted benign variants were also identified for the CHD7, WDR11 and FGF17 genes. Conclusion: Although PROP1 defects account for a majority of CPHD patients, identification of rare, less frequent variants constitutes a big challenge. Multiple genetic factors responsible for CPHD are still awaiting discovery and therefore the usage of efficient genomic tools (i.e., whole exome sequencing) will further broaden our knowledge regarding pituitary development and function.

Molecular Insights Into the Causes of Human Thymic Hypoplasia With Animal Models.

22q11.2 deletion syndrome (DiGeorge), CHARGE syndrome, Nude/SCID and otofaciocervical syndrome type 2 (OTFCS2) are distinct clinical conditions in humans that can result in hypoplasia and occasionally, aplasia of the thymus. Thymic hypoplasia/aplasia is first suggested by absence or significantly reduced numbers of recent thymic emigrants, revealed in standard-of-care newborn screens for T cell receptor excision circles (TRECs). Subsequent clinical assessments will often indicate whether genetic mutations are causal to the low T cell output from the thymus. However, the molecular mechanisms leading to the thymic hypoplasia/aplasia in diverse human syndromes are not fully understood, partly because the problems of the thymus originate during embryogenesis. Rodent and Zebrafish models of these clinical syndromes have been used to better define the underlying basis of the clinical presentations. Results from these animal models are uncovering contributions of different cell types in the specification, differentiation, and expansion of the thymus. Cell populations such as epithelial cells, mesenchymal cells, endothelial cells, and thymocytes are variably affected depending on the human syndrome responsible for the thymic hypoplasia. In the current review, findings from the diverse animal models will be described in relation to the clinical phenotypes. Importantly, these results are suggesting new strategies for regenerating thymic tissue in patients with distinct congenital disorders.

Identification of two novel mutations in three Chinese families with Kallmann syndrome using whole exome sequencing.

Kallmann syndrome (KS) is a rare developmental disorder that manifests as congenital hypogonadotropic hypogonadism with anosmia. More than 19 genes have been found to be associated with KS. However, approximately 70% of the causes of KS remain unclear. Here, we studied seven KS patients, from three families, who had delayed puberty and olfactory bulb dysplasia. However, the families of these patients showed a range of other unique clinical features, including hearing loss, anosmia (to varying degrees) and unilateral renal agenesis. We performed whole exome sequencing and copy number variation (CNV) sequencing on samples acquired from these patients. We identified two novel mutations (c.844delC in ANOS1, c.475C>T in SOX10) and a novel trigenic pattern, PROKR2/CHD7/FEZF1 (c.337T>C in PROKR2, c.748C>G in FEZF1, c.8773G>A in CHD7). The c.844delC mutation in the ANOS1 gene was predicted to generate a truncated form of the anosmin-1 protein. SIFT and PolyPhen-2 predicted that the c.475C>T mutation in SOX10 had a damaging effect. The PROKR2 mutation (c.337T>C) was previously reported as harmful. No pathogenic copy number alterations were detected. Our study expands the genotypic and phenotypic spectrum of KS, a disease that shows considerable clinical and genetic heterogeneity. The application of whole exome sequencing could facilitate our understanding of the pathogenesis of KS.

Espectro fenotípico de Síndrome de CHARGE neonatal / Phenotypic spectrum of neonatal CHARGE syndrome

INTRODUCCIÓN: El Síndrome de CHARGE (SCH), es un síndrome genético de amplia variabilidad fenotípica, de he rencia autosómica dominante, causado por variantes patogénicas en el gen CHD7. OBJETIVO: Descri bir el amplio espectro fenotípico de un SCH neonatal, heterocigoto para el gen CDH7 y la utilidad de la secuenciación en la confirmación diagnóstica, considerando los diagnósticos diferenciales. CASO CLÍNICO: recién nacida prematura de 34 semanas, con antecedentes prenatales de polihidroamnios severo, translucencia nucal aumentada y foco hiperecogénico cardiaco, con estudio de TORCH antenatal, que descartó infección congénita. Al nacer se pesquisó parálisis facial periférica, atresia de coanas, dismorfias múltiples, cardiopatía congénita y coloboma retinocoroideo bilateral. Las neuroimágenes mostraron hipoplasia de cóclea y de canales semicirculares bilaterales e hipoplasia pontocerebelosa. Los potenciales evocados auditivos mostraron hipoacusia sensorioneural profunda derecha y anacusia izquierda. Evolucionó con hipocalcemia y alteraciones en la inmunidad, confirmándose un hipoparatiroidismo e hipoplasia de timo. El cariograma fue normal y la amplificación de sondas dependiente de ligandos múltiples (MLPA) excluyó microdeleción 22q11.2. La sospecha clínica de SCH se confirmó con la detección de una variante patogénica en el gen CHD7. CONCLUSIONES: La su perposición de características clínicas del SCH con otros síndromes genéticos requiere confirmación genética molecular considerando diferencias en evolución, terapias y riesgos de recurrencia.

INTRODUCTION: CHARGE syndrome is a genetic disorder of wide phenotypic variability, of autosomal dominant in heritance, caused by pathogenic variants in the CHD7 gene. OBJECTIVE: To describe the broad pheno typic spectrum of neonatal CHARGE syndrome, heterozygous for the CHD7 gene, and the usefulness of genome sequencing in diagnostic confirmation, considering differential diagnoses. CLINICAL CASE: 34-week preterm newborn, with severe prenatal history of polyhydramnios, increased nuchal trans- lucency, and hyperechogenic cardiac focus, with a TORCH study that ruled out congenital infection. Peripheral facial paralysis, choanal atresia, multiple dysmorphisms, congenital heart disease, and bilateral retinochoroidal coloboma were observed at birth. The neuroimaging study showed hypo plasia of the cochlea and bilateral semicircular canals, and pontocerebellar hypoplasia. The auditory evoked potentials showed deep right-sided sensorineural hearing loss and left anacusis. The patient developed hypocalcemia and immunological alterations, confirming hypoparathyroidism and thy mus hypoplasia. The karyogram was normal and 22q11.2 microdeletion was excluded through mul tiplex ligation-dependent probe amplification (MPLA). A pathogenic variant in the CHD7 gene was detected that confirmed the clinical suspicion of CHARGE syndrome. CONCLUSIONS: The overlap of clinical characteristics of CHARGE syndrome requires molecular genetic confirmation, considering differences in evolution, therapies, and recurrence risks with other genetic syndromes.