Three Novel Mutations of CHD7 Gene in Two Turkish Patients with Charge Syndrome; A Double Point Mutation and an Insertion

Abstract The CHARGE (coloboma, heart defects, atresia, retardation, genital, ear) syndrome is a genetic disease characterized by ocular coloboma, choanal atresia or stenosis and semicircular canal abnormalities. Most of the patients clinically diagnosed with CHARGE syndrome have mutations in chromodomain helicase DNA-binding protein 7 (CHD7) gene. The CHD7 gene is located on chromosome 8q12.1, and up to now, there are more than 500 pathogenic mutations identified in the literature. We report two patients diagnosed with CHARGE syndrome with two novel mutations in the CHD7 gene: the first patient has double consecutive novel mutations in three adjacent codons, and the other has a novel insertion.

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Prenatal Sonographic Features of CHARGE Syndrome

Diagnostics ◽

10.3390/diagnostics11030415 ◽

2021 ◽

Vol 11 (3) ◽

pp. 415

Author(s):

Kuntharee Traisrisilp ◽

Wisit Chankhunaphas ◽

Rekwan Sittiwangkul ◽

Chureerat Phokaew ◽

Vorasuk Shotelersuk ◽

...

Keyword(s):

De Novo ◽

Heart Defects ◽

Molecular Genetic ◽

Choanal Atresia ◽

Charge Syndrome ◽

Acoustic Stimulation ◽

Genetic Mutation ◽

Suspected Case ◽

Autosomal Dominant Disorder ◽

Canal Stenosis

CHARGE syndrome is a rare autosomal dominant disorder, associated with coloboma (C), heart defects (H), choanal atresia (A), retardation of growth and/or central nervous system (R), genitourinary anomalies (G) and ear abnormalities (E). Prenatal diagnosis of the syndrome is very rare but may be suspected when a combination of such abnormalities is identified. We describe a prenatally suspected case of CHARGE syndrome due to unique findings of cardiac defects (DORV) in combination with minor clues, including a structurally malformed ear with persistent non-response to an acoustic stimulation (which has never been prenatally described elsewhere), renal malrotation and growth restriction. Postnatal diagnosis was made based on confirmation of the prenatal findings and additional specific findings of bilateral coloboma, choanal atresia and ear canal stenosis. Finally, molecular genetic testing by whole exome sequencing of the neonate and her parents revealed a novel de novo heterozygous frameshift c.3506_3509dup variant in the CHD7 gene, confirming the clinical diagnosis of CHARGE syndrome. In conclusion, we describe unique prenatal features of CHARGE syndrome. Educationally, this is one of the rare examples of CHARGE syndrome, comprising all of the six specific anomalies as originally described; it is also supported by the identification of a specific genetic mutation. The identified genetic variant has never been previously reported, thereby expanding the mutational spectrum of CHD7. Finally, this case can inspire prenatal sonographers to increase awareness of subtle or minor abnormalities as genetic sonomarkers.

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De Novo Duplication in the CHD7 Gene Associated With Severe CHARGE Syndrome

Genomics Insights ◽

10.1177/1178631019839010 ◽

2019 ◽

Vol 12 ◽

pp. 117863101983901 ◽

Cited By ~ 1

Author(s):

Laura Pranckėnienė ◽

Eglė Preikšaitienė ◽

Lucie Gueneau ◽

Alexandre Reymond ◽

Vaidutis Kučinskas

Keyword(s):

Umbilical Hernia ◽

Developmental Disorder ◽

Autosomal Dominant ◽

De Novo ◽

Choanal Atresia ◽

Sensory System ◽

Charge Syndrome ◽

Linea Alba ◽

Congenital Hernia ◽

Chd7 Gene

CHARGE syndrome is an autosomal dominant developmental disorder associated with a constellation of traits involving almost every organ and sensory system, in particular congenital anomalies, including choanal atresia and malformations of the heart, inner ear, and retina. Variants in CHD7 have been shown to cause CHARGE syndrome. Here, we report the identification of a novel de novo p.Asp2119_Pro2120ins6 duplication variant in a conserved region of CHD7 in a severely affected boy presenting with 3 and 5 of the CHARGE cardinal major and minor signs, respectively, combined with congenital umbilical hernia, congenital hernia at the linea alba, mildly hypoplastic inferior vermis, slight dilatation of the lateral ventricles, prominent metopic ridge, and hypoglycemic episodes.

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A Rare Case of Vascular Ring and Coarctation of the Aorta in Association with CHARGE Syndrome

Texas Heart Institute Journal ◽

10.14503/thij-16-5819 ◽

2017 ◽

Vol 44 (2) ◽

pp. 138-140

Author(s):

Jonathan B. Wagner ◽

Joshua Q. Knowlton ◽

Peter Pastuszko ◽

Sanket S. Shah

Keyword(s):

Aortic Arch ◽

Rare Case ◽

Heart Defects ◽

Genetic Disorder ◽

Vascular Ring ◽

Choanal Atresia ◽

Coarctation Of The Aorta ◽

Charge Syndrome ◽

Rare Type ◽

Aortic Arch Anomaly

A male neonate presented with CHARGE syndrome, a multiorgan genetic disorder involving the Coloboma of the eyes, congenital Heart defects, nasal choanal Atresia, growth and development Retardation, Genitourinary disorders, and Ear anomalies and deafness. Moreover, he had a rare case of vascular ring—consisting of a right aortic arch with retroesophageal brachiocephalic artery—combined with coarctation of the mid-aortic arch. He underwent both vascular ring and aortic arch repair at our institution. To our knowledge, this is the 4th documented case of this exceedingly rare type of aortic arch anomaly combined with aortic arch obstruction. Moreover, it is the first confirmed case of these combined disorders occurring in CHARGE syndrome. This report describes a truly rare case and reveals the limitations of echocardiography in detecting complex aortic arch anomalies while illustrating the benefits of advanced imaging prior to surgical intervention.

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CHARGE syndrome patient with novel CHD7 mutation presenting with severe laryngomalacia and feeding difficulty

BMJ Case Reports ◽

10.1136/bcr-2019-233037 ◽

2020 ◽

Vol 13 (7) ◽

pp. e233037

Author(s):

Cheuk Lam Lau ◽

Yuet Yee Chee ◽

Brian Hon Yin Chung ◽

Ming Sum Rosanna Wong

Keyword(s):

Diagnostic Criteria ◽

Novel Mutation ◽

Choanal Atresia ◽

Charge Syndrome ◽

Clinical Genetics ◽

Chd7 Gene ◽

Swallowing Difficulties ◽

Major Criterion ◽

Atypical Phenotype ◽

Chd7 Mutation

We report a case of CHARGE syndrome with atypical phenotype and a novel mutation in the CHD7 gene. Laryngomalacia and swallowing difficulties are prominent features in this case. These are commonly found in patients with CHARGE syndrome and are well described in previous studies. However, with the traditional diagnostic criteria, diagnosis is difficult without the presence of coloboma or choanal atresia. Early diagnosis is possible with the aid of clinical genetics. The current diagnostic criteria would need to be broadened with the inclusion of pathogenic CHD7 variant status as a major criterion. Further research on the function of CHD7 gene may also give us more insight on the pathogenic mechanism of various clinical features of CHARGE syndrome.

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A candidate gene for choanal atresia in alpaca

Genome ◽

10.1139/g09-100 ◽

2010 ◽

Vol 53 (3) ◽

pp. 224-230 ◽

Cited By ~ 8

Author(s):

Kent M. Reed ◽

Miranda M. Bauer ◽

Kristelle M. Mendoza ◽

Aníbal G. Armién

Keyword(s):

Regulatory Gene ◽

Choanal Atresia ◽

Clinical Manifestations ◽

Charge Syndrome ◽

Abnormal Development ◽

Whole Genome Sequence ◽

Sequence Difference ◽

Coding Region ◽

Human Sequence ◽

Chd7 Gene

Choanal atresia (CA) is a common nasal craniofacial malformation in New World domestic camelids (alpaca and llama). CA results from abnormal development of the nasal passages and is especially debilitating to newborn crias. CA in camelids shares many of the clinical manifestations of a similar condition in humans (CHARGE syndrome). Herein we report on the regulatory gene CHD7 of alpaca, whose homologue in humans is most frequently associated with CHARGE. Sequence of the CHD7 coding region was obtained from a non-affected cria. The complete coding region was 9003 bp, corresponding to a translated amino acid sequence of 3000 aa. Additional genomic sequences corresponding to a significant portion of the CHD7 gene were identified and assembled from the 2× alpaca whole genome sequence, providing confirmatory sequence for much of the CHD7 coding region. The alpaca CHD7 mRNA sequence was 97.9% similar to the human sequence, with the greatest sequence difference being an insertion in exon 38 that results in a polyalanine repeat (A12). Polymorphism in this repeat was tested for association with CA in alpaca by cloning and sequencing the repeat from both affected and non-affected individuals. Variation in length of the poly-A repeat was not associated with CA. Complete sequencing of the CHD7 gene will be necessary to determine whether other mutations in CHD7 are the cause of CA in camelids.

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Charge Syndrome

10.1093/med/9780190685157.003.0003 ◽

2018 ◽

Author(s):

Pilar Mercado ◽

Jamey E. Eklund ◽

Jennifer L. Anderson

Keyword(s):

Cranial Nerve ◽

De Novo ◽

Heart Defects ◽

Choanal Atresia ◽

Semicircular Canals ◽

Charge Syndrome ◽

Chromosome 8 ◽

De Novo Mutation ◽

Diagnostic Features ◽

Equal Distribution

The major diagnostic features of CHARGE syndrome include coloboma of the eyes, choanal atresia or stenosis, distinctive external ears, cranial nerve abnormalities, and absent or small semicircular canals. The mnemonic refers to coloboma of the eye, heart defects, atresia of choanae, retardation of growth and development, cenitalia hypoplasia, and ear abnormalities and deafness. There is no defined etiology, though a de novo mutation on the CHD 7 gene located on Chromosome 8 is responsible for more than 50% of CHARGE cases. The incidence of CHARGE is about 1:10,000 live births with an equal distribution between males and females. The anesthetic implications of this syndrome are many and vary with the patient’s phenotype. A potential difficult airway, congenital heart defects, choanal atresia, and cranial nerve abnormalities present the most significant issues for the anesthesiologist. A multidisciplinary team must be established early to properly care for these complex patients.

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Identification of three novel mutations in the CHD7 gene in patients with clinical signs of typical or atypical CHARGE syndrome

International Journal of Pediatric Otorhinolaryngology ◽

10.1016/j.ijporl.2010.09.006 ◽

2010 ◽

Vol 74 (12) ◽

pp. 1441-1444 ◽

Cited By ~ 4

Author(s):

Angela Michelucci ◽

Paolo Ghirri ◽

Paola Iacopetti ◽

Maria Elena Conidi ◽

Antonella Fogli ◽

...

Keyword(s):

Clinical Signs ◽

Charge Syndrome ◽

Novel Mutations ◽

Chd7 Gene

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Molecular analysis of the CHD7 gene in CHARGE syndrome: identification of 22 novel mutations and evidence for a low contribution of large CHD7 deletions

Genetics in Medicine ◽

10.1097/gim.0b013e318156e68e ◽

2007 ◽

Vol 9 (10) ◽

pp. 690-694 ◽

Cited By ~ 31

Author(s):

Pia Vuorela ◽

Sirpa Ala-Mello ◽

Carola Saloranta ◽

Maila Penttinen ◽

Minna Pöyhönen ◽

...

Keyword(s):

Molecular Analysis ◽

Charge Syndrome ◽

Novel Mutations ◽

Chd7 Gene

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Skull Base Anatomy in Patients with Bilateral Choanal Atresia: A Radiographic Study

Journal of Neurological Surgery Part B Skull Base ◽

10.1055/s-0040-1722230 ◽

2021 ◽

Author(s):

Christopher Pool ◽

Einat Slonimsky ◽

Roshan Nayak ◽

Lisa Engle ◽

Junjia Zhu ◽

...

Keyword(s):

Congenital Anomaly ◽

Skull Base ◽

Congenital Anomalies ◽

Heart Defects ◽

Choanal Atresia ◽

Retrospective Chart Review ◽

Charge Syndrome ◽

The Face ◽

Skull Base Anatomy ◽

Skull Base Defects

Abstract Background The risk of skull base injury during choanal atresia repair can be mitigated via thorough understanding of skull base anatomy. There is a paucity of data describing differences in skull base anatomy between patients with coloboma, heart defects, atresia choanae, growth retardation, genital abnormalities, and ear abnormalities (CHARGE) syndrome and those without. Objectives The aim of this study was to measure nasal and skull base anatomy in patients with isolated bilateral choanal atresia (BCA), CHARGE syndrome, and other syndromic congenital anomalies. Methods Retrospective chart review of patients with bilateral choanal atresia and computed tomography of the face between 2001 and 2019 were evaluated. Choanal width, height, mid-nasal height, and skull base slope were measured radiographically. Differences in anatomy between healthy patients, those with CHARGE syndrome, and those with other congenital anomalies were compared. Results Twenty-one patients with BCA and relevant imaging were identified: 7 with isolated BCA, 6 with CHARGE syndrome, and 8 with other congenital anomalies. A t-test indicated insignificant difference in skull base slope, choanal height, choanal width, or mid-nasal skull base height between isolate BCA cases and patients with any congenital anomaly. When comparing CHARGE to isolated BCA cases, mid-nasal height was shorter in CHARGE patients (p = 0.03). There were no differences in measurements between patients with congenital anomalies excluding CHARGE (p > 0.05). Two patients in the congenital anomaly group were found to have bony skull base defects preoperatively. Conclusion This study represents the largest description of skull base and nasal anatomy in patients with CHARGE syndrome and BCA. Surgeons should be aware of the lower skull base in CHARGE patients to avoid inadvertent skull base injury.

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Use of Steroid-Eluting Stents after Endoscopic Repair of Choanal Atresia: A Case Series with Review

Annals of Otology Rhinology & Laryngology ◽

10.1177/0003489420928374 ◽

2020 ◽

Vol 129 (10) ◽

pp. 1003-1010

Author(s):

Lyndy J. Wilcox ◽

Matthew M. Smith ◽

Alessandro de Alarcon ◽

Madison Epperson ◽

Hayley Born ◽

...

Keyword(s):

Primary Outcome ◽

Choanal Atresia ◽

Case Series ◽

Charge Syndrome ◽

Primary Outcome Measure ◽

Drug Eluting Stent ◽

Inclusion Criteria ◽

Endoscopic Repair ◽

Surgical Interventions ◽

Drug Eluting

Objective(s): To describe a single institution’s experience with the use of steroid-eluting stents after endoscopic transnasal repair of choanal atresia. Methods: A case series with review of children who underwent choanal atresia repair at a tertiary children’s hospital from June 2017 to January 2018 was performed. Those who had a mometasone drug-eluting stent (Propel® Mini, Intersect ENT Inc., Palo Alto, CA) placed after primary or secondary choanal atresia repair at our institution were included. The primary outcome measure was need for revision surgery due to stenosis. Postoperative regimens, duration of stenting, and need for return to the operating room (OR) were also assessed. Results: Five patients with a median age of 22 months at the time of repair met inclusion criteria. Two (40%) had bilateral atresia and 3 (60%) had confirmed CHARGE syndrome. A total of 6 mometasone drug-eluting stents were used in the 5 cases. Three patients were reassessed at least once in the OR; however, the majority (57.1%) of postoperative evaluations were able to be performed in the office or bedside setting. The first and last evaluations occurred a mean of 14 and 124 days after surgery, respectively. There were no instances of restenosis, repeat surgical interventions, or stent-related complications noted. Conclusion: Placement of a mometasone drug-eluting stent is a promising method to improve postoperative results and management of choanal atresia repair by limiting the need for repeat anesthetics and OR procedures, as well as the complications of traditional stents.

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