CHD7 mutations and CHARGE syndrome: the clinical implications of an expanding phenotype

Bergman, Jorieke E. H.; Janssen, Nicole; Hoefsloot, Lies H.; Jongmans, Marjolijn C.J.; Hofstra, Robert; Ravenswaaij-Arts, Conny M. A. van

doi:10.1136/jmg.2010.087106

Cited by 276 publications

(327 citation statements)

References 64 publications

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“…A couple of pertinent findings suggest the possibility that lobule VIII‐specific foliation defects may indeed contribute to some of the deficits in motor coordination and learning frequently associated with CHARGE syndrome (Admiraal & Huygen, 1997; Bergman, Janssen et al, 2011; Sanlaville & Verloes, 2007). Lobule VIII is active during sensorimotor tasks (Stoodley & Schmahmann, 2009; Stoodley, Valera, & Schmahmann, 2012) and abnormal motor learning and function have been reported in En2 mutant mice, which have cerebellar vermis foliation defects similar to Chd7 gt/+ mice (Cheh et al, 2006; Gerlai, 1996; Joyner et al, 1991; Millen et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…The discovery of loss‐of‐function mutations in the CHD7 gene in patients with CHARGE syndrome (Janssen et al, 2012; Vissers et al, 2004), has led to significant progress in elucidating the developmental and molecular genetic mechanisms underlying specific phenotypes associated with CHARGE syndrome (Layman, Hurd, & Martin, 2010). However, CHARGE syndrome is characterized by significant variability in incidence and severity of specific abnormalities, which does not correlate with the nature of CHD7 mutation (Basson & van Ravenswaaij‐Arts, 2015; Bergman, Janssen et al, 2011; Jongmans et al, 2008). These observations implicate other genetic or non‐genetic factors, or even stochastic effects as modifiers of disease severity.…”

Section: Introductionmentioning

confidence: 99%

“…Patients with CHARGE syndrome frequently exhibit clinical signs pertaining to neurological dysfunction, which include developmental delay, motor incoordination, intellectual disability, and autistic features (Bergman, Janssen et al, 2011; Vesseur et al, 2016). Neuroanatomical anomalies have been reported in CHARGE syndrome (Becker, Stiemer, Neumann, & Entezami, 2001; Bergman, Bocca, Hoefsloot, Meiners, & van Ravenswaaij‐Arts, 2011; Issekutz, Prasad, Smith, & Blake, 2005; Lin et al, 1990; Sanlaville et al, 2006; Sanlaville & Verloes, 2007; Tellier et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome

Whittaker

Kasah

Donovan

et al. 2017

American J of Med Genetics Pt C

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Mutations in the gene encoding the ATP dependent chromatin‐remodeling factor, CHD7 are the major cause of CHARGE (Coloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital‐urinary anomalies, and Ear defects) syndrome. Neurodevelopmental defects and a range of neurological signs have been identified in individuals with CHARGE syndrome, including developmental delay, lack of coordination, intellectual disability, and autistic traits. We previously identified cerebellar vermis hypoplasia and abnormal cerebellar foliation in individuals with CHARGE syndrome. Here, we report mild cerebellar hypoplasia and distinct cerebellar foliation anomalies in a Chd7 haploinsufficient mouse model. We describe specific alterations in the precise spatio‐temporal sequence of fissure formation during perinatal cerebellar development responsible for these foliation anomalies. The altered cerebellar foliation pattern in Chd7 haploinsufficient mice show some similarities to those reported in mice with altered Engrailed, Fgf8 or Zic1 gene expression and we propose that mutations or polymorphisms in these genes may modify the cerebellar phenotype in CHARGE syndrome. Our findings in a mouse model of CHARGE syndrome indicate that a careful analysis of cerebellar foliation may be warranted in patients with CHARGE syndrome, particularly in patients with cerebellar hypoplasia and developmental delay.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome

Whittaker

Kasah

Donovan

et al. 2017

American J of Med Genetics Pt C

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“…The guidelines we present here for cranial imaging in patients with CHARGE syndrome are based on previously published neuro‐radiologic recommendations (Asakura et al, 2008; Bergman, Janssen, et al, 2011b; Fujita et al, 2009; Gregory et al, 2013; Pinto et al, 2005; Vesseur, Free, et al, 2016a) in addition to current insights in detectable neuro‐radiologic abnormalities and anatomic variants in patients with CHARGE syndrome (see Table 3). …”

Section: Overview Of Guidelines and Recommendations From Literaturementioning

confidence: 99%

“…Imaging of the semicircular canals is recommended in patients with an atypical presentation of the syndrome to decide whether CHD7 testing is warranted, or to confirm the clinical diagnosis when CHD7 testing reveals no or an unclassified variant (Bergman, Janssen, et al, 2011b). This is because aplasia or hypoplasia of the semicircular canals is present in 95% of individuals with a pathogenic variant in the CHD7 gene, making it one of its most prevalent clinical features (Abadie et al, 2000; Bauer, Goldin, & Lusk, 2002; Lemmerling et al, 1998; Morimoto et al, 2006; Tellier et al, 1998; Wiener‐Vacher, Amanou, Denise, Narcy, & Manach, 1999).…”

Section: Diagnostic Value Of Cranial Imagingmentioning

confidence: 99%

Guidelines in CHARGE syndrome and the missing link: Cranial imaging

Geus

Free

Verbist

et al. 2017

American J of Med Genetics Pt C

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“CHARGE syndrome” is a complex syndrome with high and extremely variable comorbidity. As a result, clinicians may struggle to provide accurate and comprehensive care, and this has led to the publication of several clinical surveillance guidelines and recommendations for CHARGE syndrome, based on both single case observations and cohort studies. Here we perform a structured literature review to examine all the existing advice. Our findings provide additional support for the validity of the recently published Trider checklist. We also identified a gap in literature when reviewing all guidelines and recommendations, and we propose a guideline for neuroradiological evaluation of patients with CHARGE syndrome. This is of importance, as patients with CHARGE are at risk for peri‐anesthetic complications, making recurrent imaging procedures under anesthesia a particular risk in clinical practice. However, comprehensive cranial imaging is also of tremendous value for timely diagnosis, proper treatment of symptoms and for further research into CHARGE syndrome. We hope the guideline for neuroradiological evaluation will help clinicians provide efficient and comprehensive care for individuals with CHARGE syndrome.

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Use of Whole-Exome Sequencing for Diagnosis of Limb-Girdle Muscular Dystrophy

et al. 2015

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IMPORTANCETo our knowledge, the efficacy of transferring next-generation sequencing from a research setting to neuromuscular clinics has never been evaluated.OBJECTIVE To translate whole-exome sequencing (WES) to clinical practice for the genetic diagnosis of a large cohort of patients with limb-girdle muscular dystrophy (LGMD) for whom protein-based analyses and targeted Sanger sequencing failed to identify the genetic cause of their disorder. DESIGN, SETTING, AND PARTICIPANTSWe performed WES on 60 families with LGMDs (100 exomes). Data analysis was performed between January 6 and December 19, 2014, using the xBrowse bioinformatics interface (Broad Institute). Patients with LGMD were ascertained retrospectively through the Institute for Neuroscience and Muscle Research Biospecimen Bank between 2006 and 2014. Enrolled patients had been extensively investigated via protein studies and candidate gene sequencing and remained undiagnosed. Patients presented with more than 2 years of muscle weakness and with dystrophic or myopathic changes present in muscle biopsy specimens. MAIN OUTCOMES AND MEASURESThe diagnostic rate of LGMD in Australia and the relative frequencies of the different LGMD subtypes. Our central goals were to improve the genetic diagnosis of LGMD, investigate whether the WES platform provides adequate coverage of known LGMD-related genes, and identify new LGMD-related genes.RESULTS With WES, we identified likely pathogenic mutations in known myopathy genes for 27 of 60 families. Twelve families had mutations in known LGMD-related genes. However, 15 families had variants in disease-related genes not typically associated with LGMD, highlighting the clinical overlap between LGMD and other myopathies. Common causes of phenotypic overlap were due to mutations in congenital muscular dystrophy-related genes (4 families) and collagen myopathy-related genes (4 families). Less common myopathies included metabolic myopathy (2 families), congenital myasthenic syndrome (DOK7), congenital myopathy (ACTA1), tubular aggregate myopathy (STIM1), myofibrillar myopathy (FLNC), and mutation of CHD7, usually associated with the CHARGE syndrome. Inclusion of family members increased the diagnostic efficacy of WES, with a diagnostic rate of 60% for "trios" (an affected proband with both parents) vs 40% for single probands. A follow-up screening of patients whose conditions were undiagnosed on a targeted neuromuscular disease-related gene panel did not improve our diagnostic yield. CONCLUSIONS AND RELEVANCEWith WES, we achieved a diagnostic success rate of 45.0% in our difficult-to-diagnose cohort of patients with LGMD. We expand the clinical phenotypes associated with known myopathy genes, and we stress the importance of accurate clinical examination and histopathological results for interpretation of WES, with many diagnoses requiring follow-up review and ancillary investigations of biopsy specimens or serum samples.

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CHD7 mutations and CHARGE syndrome: the clinical implications of an expanding phenotype

Abstract: Background CHARGE syndrome is a highly variable, multiple congenital anomaly

Cited by 276 publications

References 64 publications

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome

Guidelines in CHARGE syndrome and the missing link: Cranial imaging

Use of Whole-Exome Sequencing for Diagnosis of Limb-Girdle Muscular Dystrophy

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