Erica Gerkes | University Medical Center Groningen (original) (raw)

Papers by Erica Gerkes

Research paper thumbnail of Additional file 5: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Table S5. Quality information of the WES technology, with the mean target coverage, and the % of ... more Table S5. Quality information of the WES technology, with the mean target coverage, and the % of bases with >â 20Ă coverage. (XLSX 22 kb)

Research paper thumbnail of Additional file 4: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Table S4. (A) The number of patients with isolated or combined infections, and (B) the number of ... more Table S4. (A) The number of patients with isolated or combined infections, and (B) the number of patients with isolated or combined immunophenotypes, and the percentage for which we have reported a genetic diagnosis. (XLSX 11 kb)

Research paper thumbnail of Additional file 3: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Table S3. Variants of unknown significance (class 3) and variants in TRAF3 identified in 17 patie... more Table S3. Variants of unknown significance (class 3) and variants in TRAF3 identified in 17 patients suffering from primary immunodeficiencies. (XLSX 11 kb)

Research paper thumbnail of Additional file 2: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Table S2. Shows all causative mutations identified in 72 patients from 68 families suffering from... more Table S2. Shows all causative mutations identified in 72 patients from 68 families suffering from primary immunodeficiencies. (XLSX 17 kb)

Research paper thumbnail of Additional file 1: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Table S1. Overview of all clinical characteristics of the patients included in our diagnostic PID... more Table S1. Overview of all clinical characteristics of the patients included in our diagnostic PID cohort, including all immunophenotype characteristics. (XLSX 63 kb)

Research paper thumbnail of Additional file 6: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Table S6. Information on all large >â 5-Mb homozygous regions per patient, detected in the exo... more Table S6. Information on all large >â 5-Mb homozygous regions per patient, detected in the exome. Of each region, the genomic location, size, % homozygous variants, and the detected mutation are provided. (XLSX 158 kb)

Research paper thumbnail of Additional file 7: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Additional material and references. (DOCX 31 kb)

Research paper thumbnail of Positive effect of sodium channel blocking anti-epileptic drugs on neonatal-infantile epilepsy due to a SCN2A mutation

Research paper thumbnail of Genome sequencing in families with congenital limb malformations

Human Genetics, 2021

The extensive clinical and genetic heterogeneity of congenital limb malformation calls for compre... more The extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing. We also developed a framework to identify potential noncoding pathogenic variants. We identified likely pathogenic/disease-associated variants in 12 cases (17.4%) including four in known disease genes, and one repeat expansion in HOXD13. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex stru...

Research paper thumbnail of ZMYND11 ‐related syndromic intellectual disability: 16 patients delineating and expanding the phenotypic spectrum

Research paper thumbnail of Primrose syndrome: Characterization of the phenotype in 42 patients

Research paper thumbnail of Variants in nuclear factor I genes influence growth and development

American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 2019

Research paper thumbnail of Correction: The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin–Siris syndrome

Genetics in Medicine, 2019

Research paper thumbnail of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Research paper thumbnail of Clinical and genetic characterization of individuals with predicted deleterious PHIP variants

Molecular Case Studies, 2019

Heterozygous deleterious variants in PHIP have been associated with behavioral problems, intellec... more Heterozygous deleterious variants in PHIP have been associated with behavioral problems, intellectual disability/developmental delay, obesity/overweight, and dysmorphic features (BIDOD syndrome). We report an additional 10 individuals with pleckstrin homology domain-interacting protein (PHIP)-predicted deleterious variants (four frameshift, three missense, two nonsense, and one splice site; six of which are confirmed de novo). The mutation spectrum is diverse, and there is no clustering of mutations across the protein. The clinical phenotype of these individuals is consistent with previous reports and includes behavioral problems, intellectual disability, developmental delay, hypotonia, and dysmorphic features. The additional individuals we report have a lower frequency of obesity than previous reports and a higher frequency of gastrointestinal problems, social deficits, and behavioral challenges. Characterizing additional individuals with diverse mutations longitudinally will provi...

Research paper thumbnail of The phenotypic spectrum of proximal 6q deletions based on a large cohort derived from social media and literature reports

European Journal of Human Genetics, 2018

Research paper thumbnail of Improving the diagnostic yield of exome-sequencing, by predicting gene-phenotype associations using large-scale gene expression analysis

Clinical interpretation of exome and genome sequencing data remains challenging and time consumin... more Clinical interpretation of exome and genome sequencing data remains challenging and time consuming, with many variants with unknown effects found in genes with unknown functions. Automated prioritization of these variants can improve the speed of current diagnostics and identify previously unknown disease genes. Here, we used 31,499 RNA-seq samples to predict the phenotypic consequences of variants in genes. We developed GeneNetwork Assisted Diagnostic Optimization (GADO), a tool that uses these predictions in combination with a patient’s phenotype, denoted using HPO terms, to prioritize identified variants and ease interpretation. GADO is unique because it does not rely on existing knowledge of a gene and can therefore prioritize variants missed by tools that rely on existing annotations or pathway membership. In a validation trial on patients with a known genetic diagnosis, GADO prioritized the causative gene within the top 3 for 41% of the cases. Applying GADO to a cohort of 38 p...

Research paper thumbnail of The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin–Siris syndrome

Genetics in Medicine, 2018

Research paper thumbnail of Missense Mutations of the Pro65 Residue of PCGF2 Cause a Recognizable Syndrome Associated with Craniofacial, Neurological, Cardiovascular, and Skeletal Features

The American Journal of Human Genetics, 2018

PCGF2 encodes the polycomb group ring finger 2 protein, a transcriptional repressor involved in c... more PCGF2 encodes the polycomb group ring finger 2 protein, a transcriptional repressor involved in cell proliferation, differentiation and embryogenesis. PCGF2 is a component of the polycomb repressive complex 1 (PRC1), a multiprotein complex which controls gene silencing through histone modification and chromatin remodelling. We report the phenotypic characterization of 13 patients (eleven unrelated individuals and a pair of monozygotic twins) with missense mutations in PCGF2. All mutations affected the same highly conserved proline in PCGF2 and were de novo, excepting maternal mosaicism in one. The patients demonstrated a recognisable facial gestalt, intellectual disability, feeding problems, impaired growth, and a range of brain, cardiovascular, and skeletal abnormalities. Computer structural modelling suggests the substitutions alter an N-terminal loop of PCGF2 critical for histone biding. Mutant PCGF2 may have dominant negative effects, sequestering PRC1 components into complexes which lack the ability to interact efficiently with histones. These findings demonstrate the important role of PCGF2 in human development and confirm that heterozygous substitutions of the Pro65 residue of PCGF2 cause a recognisable syndrome characterized by distinctive craniofacial, neurological, cardiovascular and skeletal features.

Research paper thumbnail of High Yield of Pathogenic Germline Mutations Causative or Likely Causative of the Cancer Phenotype in Selected Children with Cancer

Clinical cancer research : an official journal of the American Association for Cancer Research, 2018

In many children with cancer and characteristics suggestive of a genetic predisposition syndrome,... more In many children with cancer and characteristics suggestive of a genetic predisposition syndrome, the genetic cause is still unknown. We studied the yield of pathogenic mutations by applying whole-exome sequencing on a selected cohort of children with cancer. To identify mutations in known and novel cancer-predisposing genes, we performed trio-based whole-exome sequencing on germline DNA of 40 selected children and their parents. These children were diagnosed with cancer and had at least one of the following features: (1) intellectual disability and/or congenital anomalies, (2) multiple malignancies, (3) family history of cancer, or (4) an adult type of cancer. We first analyzed the sequence data for germline mutations in 146 known cancer-predisposing genes. If no causative mutation was found, the analysis was extended to the whole exome. Four patients carried causative mutations in a known cancer-predisposing gene: and ( = 3). In another 4 patients, exome sequencing revealed mutati...

Research paper thumbnail of Additional file 5: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Table S5. Quality information of the WES technology, with the mean target coverage, and the % of ... more Table S5. Quality information of the WES technology, with the mean target coverage, and the % of bases with >â 20Ă coverage. (XLSX 22 kb)

Research paper thumbnail of Additional file 4: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Table S4. (A) The number of patients with isolated or combined infections, and (B) the number of ... more Table S4. (A) The number of patients with isolated or combined infections, and (B) the number of patients with isolated or combined immunophenotypes, and the percentage for which we have reported a genetic diagnosis. (XLSX 11 kb)

Research paper thumbnail of Additional file 3: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Table S3. Variants of unknown significance (class 3) and variants in TRAF3 identified in 17 patie... more Table S3. Variants of unknown significance (class 3) and variants in TRAF3 identified in 17 patients suffering from primary immunodeficiencies. (XLSX 11 kb)

Research paper thumbnail of Additional file 2: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Table S2. Shows all causative mutations identified in 72 patients from 68 families suffering from... more Table S2. Shows all causative mutations identified in 72 patients from 68 families suffering from primary immunodeficiencies. (XLSX 17 kb)

Research paper thumbnail of Additional file 1: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Table S1. Overview of all clinical characteristics of the patients included in our diagnostic PID... more Table S1. Overview of all clinical characteristics of the patients included in our diagnostic PID cohort, including all immunophenotype characteristics. (XLSX 63 kb)

Research paper thumbnail of Additional file 6: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Table S6. Information on all large >â 5-Mb homozygous regions per patient, detected in the exo... more Table S6. Information on all large >â 5-Mb homozygous regions per patient, detected in the exome. Of each region, the genomic location, size, % homozygous variants, and the detected mutation are provided. (XLSX 158 kb)

Research paper thumbnail of Additional file 7: of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Additional material and references. (DOCX 31 kb)

Research paper thumbnail of Positive effect of sodium channel blocking anti-epileptic drugs on neonatal-infantile epilepsy due to a SCN2A mutation

Research paper thumbnail of Genome sequencing in families with congenital limb malformations

Human Genetics, 2021

The extensive clinical and genetic heterogeneity of congenital limb malformation calls for compre... more The extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing. We also developed a framework to identify potential noncoding pathogenic variants. We identified likely pathogenic/disease-associated variants in 12 cases (17.4%) including four in known disease genes, and one repeat expansion in HOXD13. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex stru...

Research paper thumbnail of ZMYND11 ‐related syndromic intellectual disability: 16 patients delineating and expanding the phenotypic spectrum

Research paper thumbnail of Primrose syndrome: Characterization of the phenotype in 42 patients

Research paper thumbnail of Variants in nuclear factor I genes influence growth and development

American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 2019

Research paper thumbnail of Correction: The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin–Siris syndrome

Genetics in Medicine, 2019

Research paper thumbnail of Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Research paper thumbnail of Clinical and genetic characterization of individuals with predicted deleterious PHIP variants

Molecular Case Studies, 2019

Heterozygous deleterious variants in PHIP have been associated with behavioral problems, intellec... more Heterozygous deleterious variants in PHIP have been associated with behavioral problems, intellectual disability/developmental delay, obesity/overweight, and dysmorphic features (BIDOD syndrome). We report an additional 10 individuals with pleckstrin homology domain-interacting protein (PHIP)-predicted deleterious variants (four frameshift, three missense, two nonsense, and one splice site; six of which are confirmed de novo). The mutation spectrum is diverse, and there is no clustering of mutations across the protein. The clinical phenotype of these individuals is consistent with previous reports and includes behavioral problems, intellectual disability, developmental delay, hypotonia, and dysmorphic features. The additional individuals we report have a lower frequency of obesity than previous reports and a higher frequency of gastrointestinal problems, social deficits, and behavioral challenges. Characterizing additional individuals with diverse mutations longitudinally will provi...

Research paper thumbnail of The phenotypic spectrum of proximal 6q deletions based on a large cohort derived from social media and literature reports

European Journal of Human Genetics, 2018

Research paper thumbnail of Improving the diagnostic yield of exome-sequencing, by predicting gene-phenotype associations using large-scale gene expression analysis

Clinical interpretation of exome and genome sequencing data remains challenging and time consumin... more Clinical interpretation of exome and genome sequencing data remains challenging and time consuming, with many variants with unknown effects found in genes with unknown functions. Automated prioritization of these variants can improve the speed of current diagnostics and identify previously unknown disease genes. Here, we used 31,499 RNA-seq samples to predict the phenotypic consequences of variants in genes. We developed GeneNetwork Assisted Diagnostic Optimization (GADO), a tool that uses these predictions in combination with a patient’s phenotype, denoted using HPO terms, to prioritize identified variants and ease interpretation. GADO is unique because it does not rely on existing knowledge of a gene and can therefore prioritize variants missed by tools that rely on existing annotations or pathway membership. In a validation trial on patients with a known genetic diagnosis, GADO prioritized the causative gene within the top 3 for 41% of the cases. Applying GADO to a cohort of 38 p...

Research paper thumbnail of The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin–Siris syndrome

Genetics in Medicine, 2018

Research paper thumbnail of Missense Mutations of the Pro65 Residue of PCGF2 Cause a Recognizable Syndrome Associated with Craniofacial, Neurological, Cardiovascular, and Skeletal Features

The American Journal of Human Genetics, 2018

PCGF2 encodes the polycomb group ring finger 2 protein, a transcriptional repressor involved in c... more PCGF2 encodes the polycomb group ring finger 2 protein, a transcriptional repressor involved in cell proliferation, differentiation and embryogenesis. PCGF2 is a component of the polycomb repressive complex 1 (PRC1), a multiprotein complex which controls gene silencing through histone modification and chromatin remodelling. We report the phenotypic characterization of 13 patients (eleven unrelated individuals and a pair of monozygotic twins) with missense mutations in PCGF2. All mutations affected the same highly conserved proline in PCGF2 and were de novo, excepting maternal mosaicism in one. The patients demonstrated a recognisable facial gestalt, intellectual disability, feeding problems, impaired growth, and a range of brain, cardiovascular, and skeletal abnormalities. Computer structural modelling suggests the substitutions alter an N-terminal loop of PCGF2 critical for histone biding. Mutant PCGF2 may have dominant negative effects, sequestering PRC1 components into complexes which lack the ability to interact efficiently with histones. These findings demonstrate the important role of PCGF2 in human development and confirm that heterozygous substitutions of the Pro65 residue of PCGF2 cause a recognisable syndrome characterized by distinctive craniofacial, neurological, cardiovascular and skeletal features.

Research paper thumbnail of High Yield of Pathogenic Germline Mutations Causative or Likely Causative of the Cancer Phenotype in Selected Children with Cancer

Clinical cancer research : an official journal of the American Association for Cancer Research, 2018

In many children with cancer and characteristics suggestive of a genetic predisposition syndrome,... more In many children with cancer and characteristics suggestive of a genetic predisposition syndrome, the genetic cause is still unknown. We studied the yield of pathogenic mutations by applying whole-exome sequencing on a selected cohort of children with cancer. To identify mutations in known and novel cancer-predisposing genes, we performed trio-based whole-exome sequencing on germline DNA of 40 selected children and their parents. These children were diagnosed with cancer and had at least one of the following features: (1) intellectual disability and/or congenital anomalies, (2) multiple malignancies, (3) family history of cancer, or (4) an adult type of cancer. We first analyzed the sequence data for germline mutations in 146 known cancer-predisposing genes. If no causative mutation was found, the analysis was extended to the whole exome. Four patients carried causative mutations in a known cancer-predisposing gene: and ( = 3). In another 4 patients, exome sequencing revealed mutati...