Publications by authors named "Addie I Nesbitt"

7 Publications

  • Page 1 of 1

A Transparent Approach to Calculate Detection Rate and Residual Risk for Carrier Screening.

J Mol Diagn 2021 01;23(1):91-102

Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pathology and Laboratory Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Electronic address:

Carrier screening involves detection of carrier status for genes associated with recessive conditions. A negative carrier screening test result bears a nonzero residual risk (RR) for the individual to have an affected child. The RR depends on the prevalence of specific conditions and the detection rate (DR) of the test itself. Herein, we provide a detailed approach for calculating DR and RR. DR was calculated on the basis of the sum of disease allele frequencies (DAFs) of pathogenic variants found in published literature. As a proof of concept, DAF data for cystic fibrosis were compared with society guidelines. The DAF data calculated by this method were consistent with the published cystic fibrosis guideline. In addition, we compared DAF for four genes (ABCC8, ASPA, GAA, and MMUT) across three laboratories, and outlined the likely reasons for discrepancies between these laboratories. The utility of carrier screening is to support couples with information while making reproductive choices. Accurate development of DR and RR is therefore critical. The method described herein provides an unbiased and transparent process to collect, calculate, and report these data.
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http://dx.doi.org/10.1016/j.jmoldx.2020.10.009DOI Listing
January 2021

Automated Clinical Exome Reanalysis Reveals Novel Diagnoses.

J Mol Diagn 2019 01;21(1):38-48

Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Clinical exome sequencing (CES) has a reported diagnostic yield of 20% to 30% for most clinical indications. The ongoing discovery of novel gene-disease and variant-disease associations are expected to increase the diagnostic yield of CES. Performing systematic reanalysis of previously nondiagnostic CES samples represents a significant challenge for clinical laboratories. Here, we present the results of a novel automated reanalysis methodology applied to 300 CES samples initially analyzed between June 2014 and September 2016. Application of our reanalysis methodology reduced reanalysis variant analysis burden by >93% and correctly captured 70 of 70 previously identified diagnostic variants among 60 samples with previously identified diagnoses. Notably, reanalysis of 240 initially nondiagnostic samples using information available on July 1, 2017, revealed 38 novel diagnoses, representing a 15.8% increase in diagnostic yield. Modeling monthly iterative reanalysis of 240 nondiagnostic samples revealed a diagnostic rate of 0.57% of samples per month. Modeling the workload required for monthly iterative reanalysis of nondiagnostic samples revealed a variant analysis burden of approximately 5 variants/month for proband-only and approximately 0.5 variants/month for trio samples. Approximately 45% of samples required evaluation during each monthly interval, and 61.3% of samples were reevaluated across three consecutive reanalyses. In sum, automated reanalysis methods can facilitate efficient reevaluation of nondiagnostic samples using up-to-date literature and can provide significant value to clinical laboratories.
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http://dx.doi.org/10.1016/j.jmoldx.2018.07.008DOI Listing
January 2019

A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis.

Am J Hum Genet 2018 05 12;102(5):995-1007. Epub 2018 Apr 12.

University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 RB Groningen, the Netherlands.

Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis.
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http://dx.doi.org/10.1016/j.ajhg.2018.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986694PMC
May 2018

De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability.

Am J Hum Genet 2017 Nov;101(5):768-788

Nottingham Regional Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, The Gables, Hucknall Road, Nottingham NG5 1PB, UK.

Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.
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http://dx.doi.org/10.1016/j.ajhg.2017.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673671PMC
November 2017

WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features.

Am J Hum Genet 2017 Jul;101(1):139-148

Division of Medical Genetics, Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.

We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. Together, these features comprise a recognizable facial phenotype. We compared these features with those of chromosome 1q41q42 microdeletion syndrome, which typically contains WDR26, and noted that clinical features are consistent between the two subsets, suggesting that haploinsufficiency of WDR26 contributes to the pathology of 1q41q42 microdeletion syndrome. Consistent with this, WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels. We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein. Given that WDR26 mutations have been identified in ∼1 in 2,000 of subjects in our clinical cohorts and that WDR26 might be poorly annotated in exome variant-interpretation pipelines, we would anticipate that this disorder could be more common than currently appreciated.
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http://dx.doi.org/10.1016/j.ajhg.2017.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501873PMC
July 2017

SPATA5 mutations cause a distinct autosomal recessive phenotype of intellectual disability, hypotonia and hearing loss.

Orphanet J Rare Dis 2016 Sep 29;11(1):130. Epub 2016 Sep 29.

Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, 91054, Erlangen, Germany.

We examined an extended, consanguineous family with seven individuals with severe intellectual disability and microcephaly. Further symptoms were hearing loss, vision impairment, gastrointestinal disturbances, and slow and asymmetric waves in the EEG. Linkage analysis followed by exome sequencing revealed a homozygous variant in SPATA5 (c.1822_1824del; p.Asp608del), which segregates with the phenotype in the family. Molecular modelling suggested a deleterious effect of the identified alterations on the protein function. In an unrelated family, we identified compound heterozygous variants in SPATA5 (c.[2081G > A];[989_991delCAA]; p.[Gly694Glu];[.Thr330del]) in a further individual with global developmental delay, infantile spasms, profound dystonia, and sensorineural hearing loss. Molecular modelling suggested an impairment of protein function in the presence of both variants.SPATA5 is a member of the ATPase associated with diverse activities (AAA) protein family and was very recently reported in one publication to be mutated in individuals with intellectual disability, epilepsy and hearing loss. Our results describe new, probably pathogenic variants in SPATA5 that were identified in individuals with a comparable phenotype. We thus independently confirm that bi-allelic pathogenic variants in SPATA5 cause a syndromic form of intellectual disability, and we delineate its clinical presentation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5041579PMC
http://dx.doi.org/10.1186/s13023-016-0509-9DOI Listing
September 2016
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