Classification of CHD7 Rare Variants in Chinese Congenital Hypogonadotropic Hypogonadism Patients and Analysis of Their Clinical Characteristics

Purpose:CHD7 rare variants can cause congenital hypogonadotropic hypogonadism (CHH) and CHARGE syndrome. We aimed to summarize the genotype and phenotype characteristics of CHH patients with CHD7 rare variants.Methods: Rare sequencing variants (RSVs) were detected by Sanger sequencing in a series of 327 CHH patients and were interpreted and grouped according to the American College of Medical Genetics and Genomics (ACMG) guideline. Detailed phenotyping and genotype-phenotype correlation were analyzed.Results: The RSV detection rate was 11.01% (36/327) in the CHH patients. We identified 30 RSVs and 19 of them were novel. Following ACMG criteria, three variants were pathogenic (P), 4 were likely pathogenic (LP), 3 were of uncertain significance with paradoxical evidence (US1), and 20 were of uncertain significance without enough evidence (US2). All patients (4/4, 100%) with P or LP variants manifested extragonadal symptoms.Conclusion: Addition of 19 novel CHD7 variants expanded the spectrum of variants, and pathogenic or likely pathogenic RSVs were more likely to cause syndromic CHH. For CHH patients carrying CHD7 RSVs, detailed genotyping and phenotyping can facilitate clinical diagnosis and therapy.

Phenotypic spectrum of patients with mutations in CHD7: clinical implications of endocrinological findings

Objective: Heterozygous CHD7 mutations cause a broad spectrum of clinical phenotypes ranging from typical CHARGE syndrome to self-limited delayed puberty. This study aimed to investigate the clinical characteristics of endocrine dysfunction in patients with CHD7 mutations. Methods: The clinical features and endocrine findings from 30 patients with CHD7 variants were retrospectively reviewed. A diagnosis of CHARGE syndrome was based on the Verloes diagnostic criteria. Results: Seventeen patients fulfilled the criteria for typical CHARGE syndrome, one patient for partial/incomplete CHARGE, and the remaining 11 patients had atypical CHARGE syndrome. One patient was diagnosed with Kallmann syndrome and unilateral deafness. The most frequently observed features were inner ear anomalies (80.0%), intellectual disability (76.7%), and external ear anomalies (73.3%). The mean height and weight SDSs at diagnosis were -2.6 ± 1.3 and -2.2 ± 1.8, respectively. Short stature was apparent in 18 patients (60%), and one patient was diagnosed with growth hormone deficiency. Seventeen males showed genital hypoplasia, including micropenis, cryptorchidism, or both. Seven patients after pubertal age had hypogonadotropic hypogonadism with hyposmia/anosmia and olfactory bulb hypoplasia. Truncating CHD7 mutations were the most common (n = 22), followed by missense variants (n = 3), splice-site variants (n = 2), and large deletion (n = 2). Conclusions: A diverse phenotypic spectrum was observed in patients with CHD7 variants, and endocrine defects such as short stature and delayed puberty occurred in most patients. Endocrine evaluation, especially for growth and pubertal impairment, should be performed during diagnosis and follow-up to improve the patient’s quality of life.

LncRNA-DRSGN (Down-Regulated in Spiral Ganglion Neurons) Competes with miR-27a for Binding to FAM172A, Supervises SGN Degeneration and ER (Endoplasmic Reticulum) Stress-Autophagy in CHARGE Syndrome

Background: Hearing loss is one of the most common disabilities in the world and brings a heavy burden to society. The current model is not stable enough, and it has caused serious model interference to clarify the pathogenesis of CHARGE syndrome. Methods: The knockout mouse model of FAM172A gene was constructed, and sits phenotype was identified. Besides, the next-genesequencing experiments of noncoding RNAs were performed utilizing the primary SGNs of model mice. The biofunctions of FAM172A in the relationships between ER (Endoplasmic reticulum) stress, autophagy, and intracellular calcium flux were investigated. Moreover, the above role associated with the competitive combination among LncRNA-DRSGN, miR-27a, and FAM172A were studied in the progression of SGN degeneration and autophagy in the model of CHARGE syndrome. Results: FAM172A(-/-) exhibited abnormal hearing, growth retardation, abnormal eye development, and dysgnosia. It was in line with the phenotype of CHARGE syndrome. Moreover, there was degeneration of SGNs in FAM172A(-/-) mice, and the differential expression of noncoding RNAs in primary SGNs were found and identified, including miR-27a and LncRNA-DRSGN. LncRNA-DRSGN regulated miR-27a as a ceRNA, and miR-27a inhibited FAM172A expression, LncRNA-DRSGN competed with miR-27a for binding to FAM172A, which participated in the regulation of ER stress-related calcium flux. LncRNA-DRSGN regulated the autophagy process of neurons by competing with miR-27a for binding to FAM172A. Conclusion: LncRNA-DRSGN competed with miR-27a for binding to FAM172A, participated in regulating ER stress-related calcium flux, then affected neuron degeneration and autophagy process of SGNs in the model of CHARGE syndrome.

An aborted case suspected to CHARGE Syndrome; A rare case with cardiac, intestinal and kidney abnormalities

Background CHARGE syndrome is a life-threatening congenital anomaly. The syndrome associations consist of coloboma, heart disease, atresia of the choanae, retarded growth and development, genital hypoplasia/genitourinary anomalies, and ear anomalies and or hearing loss. The aim of this paper is to describe and discuss a rare case of CHARGE syndrome. Case presentation During the routine dissection, atrial septal defect, overriding aorta from both ventricles, patent ductus arteriosus, duodenal anomaly, absent pancreas, right side descending and sigmoid, intestinal herniation in lesser sac, and left kidney anomaly were observed. Conclusions This rare case is of importance in re-considering the criteria of CHARGE and understanding the importance of the orchestrated morphologic driving forces of embryonic development.

Ebstein Anomaly and Right Aortic Arch in Patient with Charge Syndrome

Ebstein anomaly is a rare congenital heart disease characterized by a varying degree of anatomical and functional abnormalities of tricuspid valve and right ventricle. It often coexists with other congenital cardiac malformations. Up to 79–89% of patients with Ebstein anomaly have interatrial communication in the form of patent oval foramen or atrial septal defect and more than one-third has other types of cardiac malformations. Association between Ebstein anomaly and right aortic arch is extremely rare and only few cases have been described in the literature so far. Much rarer than with other cardiac malformations, Ebstein anomaly is associated with non-cardiac malformations or genetic syndromes. Several cases of association between Ebstein anomaly and Charge syndrome have been reported, nevertheless, Ebstein anomaly accounts for less than 1% of cardiac defects seen in patients with Charge syndrome. In this case report, we present a unique case of a patient with Charge syndrome where both Ebstein anomaly and right aortic arch are present. The diagnosis of Ebstein anomaly and right aortic arch was established prenatally. In the first years of life, the patient did not exhibit any remarkable symptoms. However, over time, deterioration of right ventricle function and increased tricuspid regurgitation were observed, requiring consideration of surgical treatment at the age of five. In addition, delay in physical, motor, and mental development was observed and thus, at the age of five, the patient was consulted by a medical geneticist and a gene panel to test for structural heart defects was ordered. The test showed a mutation in chromodomain helicase DNA binding protein 7 (CHD7) gene, which, along with clinical features, allowed to establish a diagnosis of Charge syndrome. To the best of the authors’ knowledge, this is the first case report of a patient with Charge syndrome, Ebstein anomaly, and right aortic arch that has been described in the literature.

Affordances for Motor Development in the Home Environment for Young Children with and without CHARGE Syndrome

Affordances in the home environment are critical to early motor development. Currently, the home environment has not been examined in children with deafblindness or severe disabilities. The present study examined differences in, and relationships between, the home environment and motor development in children with and without CHARGE syndrome. CHARGE syndrome is a low-incidence, complex disorder with sensory and motor impairments. Participants included 28 parents of children with CHARGE syndrome and 32 parents of children without disabilities. Children with CHARGE syndrome achieved motor milestones significantly later and had fewer outside space affordances than children without disabilities. Older children had a greater variety of stimulation and fine motor toys, and those that achieved independent walking later had more outside space and fine and gross motor toys. Early experiences may be more important for children with CHARGE syndrome than children without disabilities. Moreover, parents can play a vital role in their children’s motor development to help them reach their motor milestones.

HERVH-derived lncRNAs negatively regulate chromatin targeting and remodeling mediated by CHD7

Chd7 encodes an ATP-dependent chromatin remodeler which has been shown to target specific genomic loci and alter local transcription potentially by remodeling chromatin structure. De novo mutations in CHD7 are the major cause of CHARGE syndrome which features multiple developmental defects. We examined whether nuclear RNAs might contribute to its targeting and function and identified a preferential interaction between CHD7 and lncRNAs derived from HERVH loci in pluripotent stem cells. Knockdown of HERVH family lncRNAs using LNAs or knockout of an individual copy of HERVH by CRISPR-Cas9 both resulted in increased binding of CHD7 and increased levels of H3K27ac at a subset of enhancers. Depletion of HERVH family RNAs led to the activation of multiple genes. CHD7 bound HERVH RNA with high affinity but low specificity and this interaction decreased the ability of CHD7 to bind and remodel nucleosomes. We present a model in which HERVH lncRNAs act as a decoy to modulate the dynamics of CHD7 binding to enhancers in pluripotent cells and the activation of numerous genes that might impact the differentiation process.