Publications by authors named "P Y Billie Au"

106 Publications

Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy.

Hum Genet 2021 May 4. Epub 2021 May 4.

CHU Sainte-Justine Research Center, Montreal, QC, H3T 1C5, Canada.

Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic-clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.
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http://dx.doi.org/10.1007/s00439-021-02283-2DOI Listing
May 2021

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome.

Am J Med Genet A 2021 Jun 30;185(6):1649-1665. Epub 2021 Mar 30.

Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.
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http://dx.doi.org/10.1002/ajmg.a.62124DOI Listing
June 2021

Familial neonatal seizures caused by the Kv7.3 selectivity filter mutation T313I.

Epilepsia Open 2020 Dec 17;5(4):562-573. Epub 2020 Oct 17.

Department of Pharmacology Alberta Diabetes Institute University of Alberta Edmonton AB Canada.

Objective: A spectrum of seizure disorders is linked to mutations in Kv7.2 and Kv7.3 channels. Linking functional effects of identified mutations to their clinical presentation requires ongoing characterization of newly identified variants. In this study, we identified and functionally characterized a previously unreported mutation in the selectivity filter of Kv7.3.

Methods: Next-generation sequencing was used to identify the Kv7.3[T313I] mutation in a family affected by neonatal seizures. Electrophysiological approaches were used to characterize the functional effects of this mutation on ion channels expressed in oocytes.

Results: Substitution of residue 313 from threonine to isoleucine (Kv7.3[T313I]) likely disrupts a critical intersubunit hydrogen bond. Characterization of the mutation in homomeric Kv7.3 channels demonstrated a total loss of channel function. Assembly in heteromeric channels (with Kv7.2) leads to modest suppression of total current when expressed in oocytes. Using a Kv7 activator with distinct effects on homomeric Kv7.2 vs heteromeric Kv7.2/Kv7.3 channels, we demonstrated that assembly of Kv7.2 and Kv7.3[T313I] generates functional channels.

Significance: Biophysical and clinical effects of the T313I mutation are consistent with Kv7.3 mutations previously identified in cases of pharmacoresponsive self-limiting neonatal epilepsy. These findings expand our description of functionally characterized Kv7 channel variants and report new methods to distinguish molecular mechanisms of channel mutations.
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http://dx.doi.org/10.1002/epi4.12438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733659PMC
December 2020

Risk Factors and Outcomes of Hospitalized Patients with Severe COVID-19 and Secondary Bloodstream Infections: A Multicenter, Case-Control Study.

Clin Infect Dis 2020 Nov 20. Epub 2020 Nov 20.

Department of Medicine, Division of Allergy/Immunology and Infectious Disease, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ.

Background: Coronavirus disease 2019 (COVID-19) has become a global pandemic. Clinical characteristics regarding secondary infections in patients with COVID-19 have been reported but detailed microbiology, risk factors and outcomes of secondary bloodstream infections (sBSI) in patients with severe COVID-19 have not been well described.

Methods: We performed a multicenter, case-control study including all hospitalized patients diagnosed with severe COVID-19 and blood cultures drawn from March 1, 2020 to May 7, 2020 at three academic medical centers in New Jersey, USA. Data collection included demographics, clinical and microbiologic variables, and patient outcomes. Risk factors and outcomes were compared between cases (sBSI) and controls (no sBSI).

Results: A total of 375 hospitalized patients were included. There were 128 sBSIs during the hospitalization. For the first set of positive blood cultures, 117 (91.4%) were bacterial and 7 (5.5%) were fungal. Those with sBSI were more likely to have altered mental status, lower mean percent oxygen saturation on room air, have septic shock and be admitted to the intensive care unit compared to the controls. In-hospital mortality was higher in those with a sBSI versus controls (53.1% vs 32.8%, p=0.0001).

Conclusions: We observed hospitalized adult patients with severe COVID-19 and sBSI had a more severe initial presentation, prolonged hospital course, and worse clinical outcomes. To maintain antimicrobial stewardship principles, further prospective studies are necessary to better characterize risk factors and prediction modeling to better understand when to suspect and empirically treat for sBSI in severe COVID-19.
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http://dx.doi.org/10.1093/cid/ciaa1748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717183PMC
November 2020

Description of neurodevelopmental phenotypes associated with 10 genetic neurodevelopmental disorders: A scoping review.

Clin Genet 2021 Mar 18;99(3):335-346. Epub 2020 Nov 18.

Cumming School of Medicine, University of Calgary, Calgary, Canada.

Neurodevelopmental disorders (NDDs) are a heterogeneous group of conditions including intellectual disability, global developmental delay, autism spectrum disorder, and attention deficit hyperactivity disorder. Advances in genetic diagnostic technology have led to the identification of a number of NDD-associated genes, but reports of cognitive and developmental outcomes in affected individuals have been variable. The objective of this scoping review is to synthesize available information pertaining to the developmental outcomes of individuals with pathogenic variants in ten emerging recurrent NDD-associated genes identified from large scale sequencing studies; ADNP, ANKRD11, ARID1B, CHD2, CHD8, CTNNB1, DDX3X, DYRK1A, SCN2A, and SYNGAP1. After a comprehensive search, 260 articles were selected that reported on neurodevelopmental measures or diagnoses. We identify the spectrum of developmental outcomes for each genetic NDD, including prevalence of intellectual disability, frequency of co-morbid NDDs such as ADHD and autism, and commonly reported medical issues that can help inform diagnosis and treatment. There are significant gaps in our understanding of the natural history of these conditions. Future research focusing on barriers to assessment, the development of modified assessment tools appropriate for long-term outcomes in genetic NDD, and collection of longitudinal data will increase understanding of prognosis in these conditions and inform evaluations of treatment.
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http://dx.doi.org/10.1111/cge.13882DOI Listing
March 2021