Human Genetics and Clinical Aspects of Neurodevelopmental Disorders

Lyon, Gholson J.; O'Rawe, Jason

doi:10.1002/9781118524947.ch13

Cited by 15 publications

(14 citation statements)

References 258 publications

(227 reference statements)

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“…Many syndromes affecting neurological development present with heterogeneous and nondistinct phenotypes (Lyon and O'Rawe 2015) and therefore remain undiagnosed or are misdiagnosed. The combination of whole-exome sequencing combined with detailed and standardized phenotypic documentation is a powerful method to achieve improved diagnoses, particularly in the context of large-scale genomic sequencing efforts of normal population controls (Lek et al 2016a).…”

Section: Discussionmentioning

confidence: 99%

“…Whole-exome sequencing (WES) is a method that mainly targets regions of the genome that code for proteins and is useful for detecting disease-contributing variants in genes associated with rare genetic syndromes (Bamshad et al 2011; Lyon and Wang 2012; Lyon and Segal 2013; Biesecker and Green 2014; Chong et al 2015; Guo et al 2015; He et al 2015; Lyon and O'Rawe 2015). Here we report our efforts in phenotypic characterization and molecular diagnosis of a previously undiagnosed pediatric patient.…”

Section: Introductionmentioning

confidence: 99%

“…The syndrome's name was derived from the last names of the first three families found to have this syndrome (Herrmann et al 1975). Our primary goal in reporting this detailed case description is to provide rich phenotypic information that is still typically missing from many studies (Hall 2003), thus enabling a better description and accounting of the tremendous variable expressivity (Lyon and O'Rawe 2015) and stochastic developmental variation (SDV) (Vogt 2015) in all diseases.…”

Section: Introductionmentioning

confidence: 99%

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KBG syndrome involving a single-nucleotide duplication in ANKRD11

Kleyner

Malcolmson

Tegay

et al. 2016

Cold Spring Harb Mol Case Stud

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KBG syndrome is a rare autosomal dominant genetic condition characterized by neurological involvement and distinct facial, hand, and skeletal features. More than 70 cases have been reported; however, it is likely that KBG syndrome is underdiagnosed because of lack of comprehensive characterization of the heterogeneous phenotypic features. We describe the clinical manifestations in a male currently 13 years of age, who exhibited symptoms including epilepsy, severe developmental delay, distinct facial features, and hand anomalies, without a positive genetic diagnosis. Subsequent exome sequencing identified a novel de novo heterozygous single base pair duplication (c.6015dupA) in ANKRD11, which was validated by Sanger sequencing. This single-nucleotide duplication is predicted to lead to a premature stop codon and loss of function in ANKRD11, thereby implicating it as contributing to the proband's symptoms and yielding a molecular diagnosis of KBG syndrome. Before molecular diagnosis, this syndrome was not recognized in the proband, as several key features of the disorder were mild and were not recognized by clinicians, further supporting the concept of variable expressivity in many disorders. Although a diagnosis of cerebral folate deficiency has also been given, its significance for the proband's condition remains uncertain.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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KBG syndrome involving a single-nucleotide duplication in ANKRD11

Kleyner

Malcolmson

Tegay

et al. 2016

Cold Spring Harb Mol Case Stud

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“…Although such analyses focus on ∼1% of the human genome, this, nonetheless, still identifies tens of thousands of variants to analyze (O'Rawe et al 2013, 2015; Lyon and O'Rawe 2015). Through the use of existing and novel bioinformatics tools, we developed a protocol focused on identifying uncommon and deleterious mutations and prioritizing them by phenotypic relevance.…”

Section: Introductionmentioning

confidence: 99%

SCN8A mutation in a child presenting with seizures and developmental delays

Malcolmson

Kleyner

Tegay

et al. 2016

Cold Spring Harb Mol Case Stud

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The SCN8A gene encodes the sodium voltage-gated channel alpha subunit 8. Mutations in this gene have been associated with early infantile epileptic encephalopathy type 13. With the use of whole-exome sequencing, a de novo missense mutation in SCN8A was identified in a 4-yr-old female who initially exhibited symptoms of epilepsy at the age of 5 mo that progressed to a severe condition with very little movement, including being unable to sit or walk on her own.

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“…While preparing a paper setting out his concerns, Weldon checked the "probable error" of Mendel's results, using a standard formula to calculate expected century goes ever further in disclosing the importance of variability, interaction, complexity and even ancestry (15). If the time is ripe for retiring the problem of Mendel's data, it is also ripe for rediscovering, and engaging with, Weldon's critique of Mendelian concepts.…”

Section: Beyond the "Mendel-fisher Controversy"mentioning

confidence: 99%