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Papers by David Buritica

Genetics in Medicine Open

American Journal of Obstetrics and Gynecology

Journal of Neurophysiology

Six novel de novo human KCNQ5 variants were identified from children with neurodevelopmental dela... more Six novel de novo human KCNQ5 variants were identified from children with neurodevelopmental delay, intellectual disability, and/or epilepsy. Expression of these variants along with four previously reported KCNQ5 variants from a similar cohort revealed GOF potassium channels, negatively shifted in V50 of activation and/or delayed deactivation kinetics. GOF is extended to KCNQ5/3 heteromeric channels, making these the predominant channels affected in heterozygous de novo patients. Kcnq5 LOF mice exhibited seizures, consistent with in vivo pathogenicity.

Mitochondrion

INTRODUCTION: The electron transport chain (ETC) in mitochondria functions to produce energy in t... more INTRODUCTION: The electron transport chain (ETC) in mitochondria functions to produce energy in the form of adenosine triphosphate (ATP). Defects in the mitochondrial or nuclear DNA that codes for components of the ETC lead to mitochondrial disorders (MTDs). MTDs are multi-system conditions affecting the heart, muscles, and especially brain. The endocrine system is commonly affected in MTDs, and diabetes and hyperglycemia are established secondary diagnoses. Rates of non-iatrogenic hypoglycemia have not been studied in individuals with MTDs. This study aims to investigate the frequency of hypoglycemia in patients with MTDs. METHODS: Individuals diagnosed with a 'definite' or 'probable' MTD according to the modified Walker criteria at The University of Texas, Mitochondrial Center of Excellence were included in this study. Exclusion criteria included diagnosis of diabetes or adrenal insufficiency or past or present use of hydrocortisone or prednisone. Patient charts were reviewed retrospectively for blood glucose values. Individuals with at least two values were recorded. Patients were classified as neonatal (≤28 days of life) or non-neonatal (>28 days of life) at the time of measurement. Data analysis included descriptive statistics, mixed-model regression, and two-sample tests of proportion. All data analysis was done using Stata® (v.13, College Station, TX). Statistical significance was assumed at p<0.05. RESULTS: Of the 116 patients included in this study, 22 (18.97%) experienced at least one episode of hypoglycemia. This is significantly higher (p<0.05) than the 6% non-diabetic, general population rate of hypoglycemia. Neonatal readings were also found to be 30mg/dL lower than non-neonatal readings, on average, a significant difference (p<0.05). iv CONCLUSION: Patients with MTD are more likely to experience hypoglycemia compared to the general population with especially low blood glucose readings during the neonatal period. This demonstrates hypoglycemia may be contributing to the high rate of neurological symptoms reported in MTDs and supports that MTDs should be on the differential diagnosis in cases of hypoglycemia, especially during the neonatal period. Additional and earlier monitoring of blood glucose could reduce negative outcomes such as decreased cognitive outcome, developmental delays, seizures, or brain damage in patients with MTDs.

Genetics in Medicine, 2022

Genetics in Medicine, 2021

PURPOSE: Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activit... more PURPOSE: Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency. METHODS: Three individuals with intellectual disability and iris anomalies and truncating de novo PRR12 variants were described previously. We add 21 individuals with similar PRR12 variants identified via matchmaking platforms, bringing the total number to 24. RESULTS: We observed 12 frameshift, 6 nonsense, 1 splice-site, and 2 missense variants and one patient with a gross deletion involving PRR12. Three individuals had additional genetic findings, possibly confounding the phenotype. All patients had developmental impairment. Variable structural eye defects were observed in 12/24 individuals (50%) including anophthalmia, microphthalmia, colobomas, optic nerve and iris abnormalities. Additional common features included hypotonia (61%), heart defects (52%), growth failure (54%), and kidney anomalies (35%). PrediXcan analysis showed that phecodes most strongly associated with reduced predicted PRR12 expression were enriched for eye-(7/30) and kidney-(4/30) phenotypes, such as wet macular degeneration and chronic kidney disease. CONCLUSION: These findings support PRR12 haploinsufficiency as a cause for a novel disorder with a wide clinical spectrum marked chiefly by neurodevelopmental and eye abnormalities.

American Journal of Medical Genetics Part A, 2021

Achondroplasia is the most common disproportionate short statured skeletal dysplasia with a preva... more Achondroplasia is the most common disproportionate short statured skeletal dysplasia with a prevalence of approximately 1:20,000–30,000. We created the largest database to date of a historical cohort of 1374 patients with achondroplasia (CLARITY—aChondropLasia nAtuRal hIsTory studY). This cohort was queried for the presence of unrecognized or under‐recognized features associated with achondroplasia. Craniosynostosis was found to co‐occur with achondroplasia in 9 (0.65%) patients in this cohort, which is much higher than the general population prevalence of 3.1–7.2 per 10,000. In addition, 27 patients had seizures (2.0%), an apparent excess as compared to the general population. Only two people had diabetes despite a high rate of adult obesity. This report documents for the first time an increased prevalence of craniosynostosis in persons with achondroplasia, and adds support to previous observations of an apparently higher than expected prevalence of seizures and lower prevalence of...

Genetics in Medicine, 2021

Purpose Achondroplasia is the most common short stature skeletal dysplasia (1:20,000–30,000), but... more Purpose Achondroplasia is the most common short stature skeletal dysplasia (1:20,000–30,000), but the risk of adverse health outcomes from cardiovascular diseases, pain, poor function, excess weight, and sleep apnea is unclear. A multicenter retrospective natural history study was conducted to understand medical and surgical practices in achondroplasia. Methods Data from patients with achondroplasia evaluated by clinical geneticists at Johns Hopkins University, A.I. duPont Hospital for Children, McGovern Medical School UTHealth, and University of Wisconsin were populated into a REDCap database. All available retrospective medical records of anthropometry (length/height, weight, occipitofrontal circumference), surgery, polysomnography (PSG), and imaging (e.g., X-ray, magnetic resonance imaging) were included. Results Data from 1,374 patients (48.8% female; mean age 15.4 ± 13.9 years) constitute the primary achondroplasia cohort (PAC) with 496 subjects remaining clinically active and ...

The Laryngoscope, 2021

Objectives/HypothesisTo quantify otolaryngologic surgery utilization in patients with achondropla... more Objectives/HypothesisTo quantify otolaryngologic surgery utilization in patients with achondroplasia, and to identify any changes in utilization over the past four decades.Study DesignRetrospective cohort study.MethodsA retrospective cohort study of 1,374 patients with achondroplasia enrolled in the CLARITY retrospective cohort study at four centers of multi‐specialty care for patients with achondroplasia. Otolaryngologic surgeries are presented by birth cohort decade. The main outcomes were number of primary and additional otolaryngologic procedures; age at surgery; likelihood of repeated surgery; temporal trends in surgical utilization.ResultsIn this cohort of 1,374 patients with achondroplasia, 620 (45.1%) had pharyngeal surgery at least once, 150 (10.9%) had pharyngeal surgery on more than one occasion, and patients who had adenoidectomy first were 2.68 times more likely to require a second pharyngeal surgery than those who had adenotonsillectomy. Seven hundred and seventy‐nine ...

Frontiers in Neurology, 2021

Background: Tuberous sclerosis complex (TSC) is a genetic condition that causes benign tumors to ... more Background: Tuberous sclerosis complex (TSC) is a genetic condition that causes benign tumors to grow in multiple organ systems. Nonfunctional pancreatic neuroendocrine tumors (PNETs) are a rare clinical feature of TSC with no specific guidelines outlined for clinical management at this time. Our purpose is to calculate the frequency of nonfunctional PNETs as well as characterize the presentation, current clinical management, and assess the impact of systemic mammalian target of rapamycin (mTOR) on nonfunctional PNETs in TSC.Methods: This retrospective chart review was performed by a query of the TS Alliance's Natural History Database and the Cincinnati Children's Hospital TSC Database for patients with nonfunctional PNET. Clinical data from these two groups was summarized for patients identified to have a nonfunctional PNET and compared to previously reported cases with TSC and nonfunctional PNETs.Results: Our calculated frequency of nonfunctional PNETs is 0.65%. We identif...

European Journal of Pediatrics, 2017

Background Adolescence represents a unique time of transition to adulthood. Our hospital group en... more Background Adolescence represents a unique time of transition to adulthood. Our hospital group encompasses 6 hospital sites catering to 100 000 individuals under 18 years of age, approximately 18 387 of which are aged between 14 and 16 years. Traditionally our Paediatric Department accepted new patients up until their 14th birthday, while those with chronic illnesses remained under Paediatric care until completion of second level education and were then transitioned to adult services. Our data addresses the concern of expanding the Paediatric field of inclusion to incorporate a growing number of adolescence and the impact this may have on the provisions of healthcare across many specialties. Objective The objective of our study is to compile data on outpatients between 14 and 16 years of age in our hospital group and to acknowledge the need to appropriately develop sustainable support models for this age group. Methods We looked at a 10 year study period between 2006 and 2016. Using the hospital's electronic database, we identified outpatient attendances of patients aged between 14 and 16 years. Details of patient demographics, symptomatology, clinic attendances and consultant(s) seen were documented. Results Over our 10-year study period 41 456 patient contacts met the criteria for inclusion, 7 828 (19 %) of these were under direct Paediatric care and 33 628 patients required assistance from other departments. Of the 25 departments offering assistance the most prevalent in order of frequency were Orthopaedics, Otolaryngology, Maxillofacial and Dermatology. Conclusion Our data highlights the demand placed on staff working in Paediatrics upon the extension of the Paediatric age profile. Future work to improve the quality of adolescent outpatient services should emphasize multidisciplinary team work whereby relevant specialties are working together under the leadership of an Adolescent Medicine Physician. Planning for health services is essential to ensure that clinical services are able to meet the current and future needs of the population it serves.

Genetics in Medicine, 2019

Purpose: Haploinsufficiency of DYRK1A causes a recognizable clinical syndrome. The goal of this p... more Purpose: Haploinsufficiency of DYRK1A causes a recognizable clinical syndrome. The goal of this paper is to investigate congenital anomalies of the kidney and urinary tract (CAKUT) and genital defects (GD) in patients with DYRK1A variants. Methods: A large database of clinical exome sequencing (ES) was queried for de novo DYRK1A variants and CAKUT/GD phenotypes were characterized. Xenopus laevis (frog) was chosen as a model organism to assess Dyrk1a's role in renal development. Results: Phenotypic details and variants of 19 patients were compiled after an initial observation that one patient with a de novo pathogenic variant in DYRK1A had GD. CAKUT/GD data were available from 15 patients, 11 of whom presented with CAKUT/GD. Studies in Xenopus embryos demonstrated that knockdown of Dyrk1a, which is expressed in forming nephrons, disrupts the development of segments of embryonic nephrons, which ultimately give rise to the entire genitourinary (GU) tract. These defects could be rescued by coinjecting wild-type human DYRK1A RNA, but not with DYRK1A R205* or DYRK1A L245R RNA. Conclusion: Evidence supports routine GU screening of all individuals with de novo DYRK1A pathogenic variants to ensure optimized clinical management. Collectively, the reported clinical data and loss-of-function studies in Xenopus substantiate a novel role for DYRK1A in GU development.

Journal of Genetic Counseling, 2019

The purpose of this study was to describe current genetic counseling practice in the United State... more The purpose of this study was to describe current genetic counseling practice in the United States following a non‐invasive prenatal testing (NIPT) result positive for a sex chromosome abnormality (SCA). Screening for SCAs can be confounded by confined placental mosaicism, natural loss of the X chromosome from maternal cells during aging, and undiagnosed maternal SCA or copy number variant (CNV). Furthermore, with the exception of 45,X, individuals with SCAs usually have no ultrasound or postnatal findings. This makes follow‐up for unresolved positive NIPT necessary; however, there are currently no clinical guidelines. This study used a cross‐sectional design with an anonymous questionnaire to survey 176 genetic counselors. The majority of prenatal respondents always offered diagnostic testing (>88%) and anatomy ultrasound (~90%), but the percent consistently offering maternal karyotype (22%–52%) and postnatal evaluation (28%–87%) varied. Maternal karyotype was offered more often...

Prenatal Diagnosis, 2019

ObjectiveWe evaluated what prenatal genetic counselor's (GCs) practices, attitudes, and barri... more ObjectiveWe evaluated what prenatal genetic counselor's (GCs) practices, attitudes, and barriers are in regards to prenatal microarray since the publication of the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal‐Fetal Medicine (SMFM) guidelines for microarray use.MethodsThis was a survey‐based cross‐sectional study of English‐speaking, board certified or eligible GCs who currently practice prenatal genetic counseling.ResultsOf 192 respondents, 183 (95%) have incorporated chromosome microarray (CMA) into clinical practice, with 64% believing that the benefits of CMA outweigh the harms and 52% agreeing that CMA should be offered to all women regardless of indication. Those who reported being experts/comfortable in their knowledge of CMA (85%) and familiar with current clinical guidelines (86%) were significantly more likely to offer CMA to patients undergoing invasive testing and patients with fetal anomalies. Patient‐specific concerns were ...

Neuro-Oncology, 2018

NEURO-ONCOLOGY • NOVEMBER 2018 of expression of SMARCAL1 in SMARCAL1-null cell lines markedly sup... more NEURO-ONCOLOGY • NOVEMBER 2018 of expression of SMARCAL1 in SMARCAL1-null cell lines markedly suppressed ALT features and was dependent on the enzyme helicase activity. Furthermore, using break-apart FISH and whole genome sequencing, we identified recurrent rearrangements upstream of TERT in ~50% of triplenegative GBMs. These TERT-rearranged tumors exhibited elevated levels of TERT mRNA expression. This represents a novel mechanism of telomerase activation in GBMs lacking the well-known TERT promoter hotspot mutations. Finally, we identify recurrent BRAF V600E mutations in younger patients with GBM. Collectively, our findings define novel molecular subgroups of glioblastoma, including a telomerase-positive subgroup driven by TERT-structural rearrangements (IDH WT-TERT SV , ~50%), and an ALTpositive subgroup (IDH WT-ALT, ~40%) with mutations in ATRX or SMAR-CAL1. We also establish SMARCAL1 inactivating mutations as a novel genetic mechanism of ALT in cancer.

Advances in chronic kidney disease, 2017

Hypertension (HT) is a public health problem in children particularly related to the epidemic of ... more Hypertension (HT) is a public health problem in children particularly related to the epidemic of overweight and obesity. Monogenic forms of HT are important in the differential diagnosis in children presenting with severe or refractory HT, who have a family history of early-onset HT, unusual physical examination findings, and/or characteristic hormonal and biochemical abnormalities. Most genetic defects in these disorders ultimately result in increased sodium transport in the distal nephron resulting in volume expansion and HT. Genetic testing, which is increasingly available, has diagnostic, therapeutic, and predictive implications for families affected by these rare conditions.

European journal of medical genetics, 2017

Marshall-Smith Syndrome (MRSHSS) is a very rare genetic disorder characterized by failure to thri... more Marshall-Smith Syndrome (MRSHSS) is a very rare genetic disorder characterized by failure to thrive and characteristic dysmorphic features associated with accelerated osseous maturation. We present a nine-year-old girl who was diagnosed with MRSHSS based on characteristic clinical features supported by the identification of a novel de novo pathogenic variant in the NFIX gene. The patient also presented with precocious puberty diagnosed at five years of age and had an abnormal GnRH stimulation test indicative of central precocious puberty. Central precocious puberty has not been described in association with MRSHSS previously in the medical literature and broadens our knowledge of the natural history of MRSHSS. The causes of advanced bone age in this syndrome are also reviewed. Additionally, the patient showed progressive dilatation of the aortic root. Although connective tissue abnormalities have been described in association with MRSHSS, aortic root dilatation has not. Understandin...

American journal of human genetics, 2017

Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in norma... more Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer...

Journal of Pediatric Endocrinology and Metabolism, 2016

Permanent neonatal diabetes (PNDM) is a rare genetic condition characterized by hyperglycemia, in... more Permanent neonatal diabetes (PNDM) is a rare genetic condition characterized by hyperglycemia, insulinopenia, and failure to thrive beginning in the first 6 months of life. Recessive mutations in

Genetics in Medicine Open

American Journal of Obstetrics and Gynecology

Journal of Neurophysiology

Six novel de novo human KCNQ5 variants were identified from children with neurodevelopmental dela... more Six novel de novo human KCNQ5 variants were identified from children with neurodevelopmental delay, intellectual disability, and/or epilepsy. Expression of these variants along with four previously reported KCNQ5 variants from a similar cohort revealed GOF potassium channels, negatively shifted in V50 of activation and/or delayed deactivation kinetics. GOF is extended to KCNQ5/3 heteromeric channels, making these the predominant channels affected in heterozygous de novo patients. Kcnq5 LOF mice exhibited seizures, consistent with in vivo pathogenicity.

Mitochondrion

INTRODUCTION: The electron transport chain (ETC) in mitochondria functions to produce energy in t... more INTRODUCTION: The electron transport chain (ETC) in mitochondria functions to produce energy in the form of adenosine triphosphate (ATP). Defects in the mitochondrial or nuclear DNA that codes for components of the ETC lead to mitochondrial disorders (MTDs). MTDs are multi-system conditions affecting the heart, muscles, and especially brain. The endocrine system is commonly affected in MTDs, and diabetes and hyperglycemia are established secondary diagnoses. Rates of non-iatrogenic hypoglycemia have not been studied in individuals with MTDs. This study aims to investigate the frequency of hypoglycemia in patients with MTDs. METHODS: Individuals diagnosed with a 'definite' or 'probable' MTD according to the modified Walker criteria at The University of Texas, Mitochondrial Center of Excellence were included in this study. Exclusion criteria included diagnosis of diabetes or adrenal insufficiency or past or present use of hydrocortisone or prednisone. Patient charts were reviewed retrospectively for blood glucose values. Individuals with at least two values were recorded. Patients were classified as neonatal (≤28 days of life) or non-neonatal (>28 days of life) at the time of measurement. Data analysis included descriptive statistics, mixed-model regression, and two-sample tests of proportion. All data analysis was done using Stata® (v.13, College Station, TX). Statistical significance was assumed at p<0.05. RESULTS: Of the 116 patients included in this study, 22 (18.97%) experienced at least one episode of hypoglycemia. This is significantly higher (p<0.05) than the 6% non-diabetic, general population rate of hypoglycemia. Neonatal readings were also found to be 30mg/dL lower than non-neonatal readings, on average, a significant difference (p<0.05). iv CONCLUSION: Patients with MTD are more likely to experience hypoglycemia compared to the general population with especially low blood glucose readings during the neonatal period. This demonstrates hypoglycemia may be contributing to the high rate of neurological symptoms reported in MTDs and supports that MTDs should be on the differential diagnosis in cases of hypoglycemia, especially during the neonatal period. Additional and earlier monitoring of blood glucose could reduce negative outcomes such as decreased cognitive outcome, developmental delays, seizures, or brain damage in patients with MTDs.

Genetics in Medicine, 2022

Genetics in Medicine, 2021

PURPOSE: Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activit... more PURPOSE: Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency. METHODS: Three individuals with intellectual disability and iris anomalies and truncating de novo PRR12 variants were described previously. We add 21 individuals with similar PRR12 variants identified via matchmaking platforms, bringing the total number to 24. RESULTS: We observed 12 frameshift, 6 nonsense, 1 splice-site, and 2 missense variants and one patient with a gross deletion involving PRR12. Three individuals had additional genetic findings, possibly confounding the phenotype. All patients had developmental impairment. Variable structural eye defects were observed in 12/24 individuals (50%) including anophthalmia, microphthalmia, colobomas, optic nerve and iris abnormalities. Additional common features included hypotonia (61%), heart defects (52%), growth failure (54%), and kidney anomalies (35%). PrediXcan analysis showed that phecodes most strongly associated with reduced predicted PRR12 expression were enriched for eye-(7/30) and kidney-(4/30) phenotypes, such as wet macular degeneration and chronic kidney disease. CONCLUSION: These findings support PRR12 haploinsufficiency as a cause for a novel disorder with a wide clinical spectrum marked chiefly by neurodevelopmental and eye abnormalities.

American Journal of Medical Genetics Part A, 2021

Achondroplasia is the most common disproportionate short statured skeletal dysplasia with a preva... more Achondroplasia is the most common disproportionate short statured skeletal dysplasia with a prevalence of approximately 1:20,000–30,000. We created the largest database to date of a historical cohort of 1374 patients with achondroplasia (CLARITY—aChondropLasia nAtuRal hIsTory studY). This cohort was queried for the presence of unrecognized or under‐recognized features associated with achondroplasia. Craniosynostosis was found to co‐occur with achondroplasia in 9 (0.65%) patients in this cohort, which is much higher than the general population prevalence of 3.1–7.2 per 10,000. In addition, 27 patients had seizures (2.0%), an apparent excess as compared to the general population. Only two people had diabetes despite a high rate of adult obesity. This report documents for the first time an increased prevalence of craniosynostosis in persons with achondroplasia, and adds support to previous observations of an apparently higher than expected prevalence of seizures and lower prevalence of...

Genetics in Medicine, 2021

Purpose Achondroplasia is the most common short stature skeletal dysplasia (1:20,000–30,000), but... more Purpose Achondroplasia is the most common short stature skeletal dysplasia (1:20,000–30,000), but the risk of adverse health outcomes from cardiovascular diseases, pain, poor function, excess weight, and sleep apnea is unclear. A multicenter retrospective natural history study was conducted to understand medical and surgical practices in achondroplasia. Methods Data from patients with achondroplasia evaluated by clinical geneticists at Johns Hopkins University, A.I. duPont Hospital for Children, McGovern Medical School UTHealth, and University of Wisconsin were populated into a REDCap database. All available retrospective medical records of anthropometry (length/height, weight, occipitofrontal circumference), surgery, polysomnography (PSG), and imaging (e.g., X-ray, magnetic resonance imaging) were included. Results Data from 1,374 patients (48.8% female; mean age 15.4 ± 13.9 years) constitute the primary achondroplasia cohort (PAC) with 496 subjects remaining clinically active and ...

The Laryngoscope, 2021

Objectives/HypothesisTo quantify otolaryngologic surgery utilization in patients with achondropla... more Objectives/HypothesisTo quantify otolaryngologic surgery utilization in patients with achondroplasia, and to identify any changes in utilization over the past four decades.Study DesignRetrospective cohort study.MethodsA retrospective cohort study of 1,374 patients with achondroplasia enrolled in the CLARITY retrospective cohort study at four centers of multi‐specialty care for patients with achondroplasia. Otolaryngologic surgeries are presented by birth cohort decade. The main outcomes were number of primary and additional otolaryngologic procedures; age at surgery; likelihood of repeated surgery; temporal trends in surgical utilization.ResultsIn this cohort of 1,374 patients with achondroplasia, 620 (45.1%) had pharyngeal surgery at least once, 150 (10.9%) had pharyngeal surgery on more than one occasion, and patients who had adenoidectomy first were 2.68 times more likely to require a second pharyngeal surgery than those who had adenotonsillectomy. Seven hundred and seventy‐nine ...

Frontiers in Neurology, 2021

Background: Tuberous sclerosis complex (TSC) is a genetic condition that causes benign tumors to ... more Background: Tuberous sclerosis complex (TSC) is a genetic condition that causes benign tumors to grow in multiple organ systems. Nonfunctional pancreatic neuroendocrine tumors (PNETs) are a rare clinical feature of TSC with no specific guidelines outlined for clinical management at this time. Our purpose is to calculate the frequency of nonfunctional PNETs as well as characterize the presentation, current clinical management, and assess the impact of systemic mammalian target of rapamycin (mTOR) on nonfunctional PNETs in TSC.Methods: This retrospective chart review was performed by a query of the TS Alliance's Natural History Database and the Cincinnati Children's Hospital TSC Database for patients with nonfunctional PNET. Clinical data from these two groups was summarized for patients identified to have a nonfunctional PNET and compared to previously reported cases with TSC and nonfunctional PNETs.Results: Our calculated frequency of nonfunctional PNETs is 0.65%. We identif...

European Journal of Pediatrics, 2017

Background Adolescence represents a unique time of transition to adulthood. Our hospital group en... more Background Adolescence represents a unique time of transition to adulthood. Our hospital group encompasses 6 hospital sites catering to 100 000 individuals under 18 years of age, approximately 18 387 of which are aged between 14 and 16 years. Traditionally our Paediatric Department accepted new patients up until their 14th birthday, while those with chronic illnesses remained under Paediatric care until completion of second level education and were then transitioned to adult services. Our data addresses the concern of expanding the Paediatric field of inclusion to incorporate a growing number of adolescence and the impact this may have on the provisions of healthcare across many specialties. Objective The objective of our study is to compile data on outpatients between 14 and 16 years of age in our hospital group and to acknowledge the need to appropriately develop sustainable support models for this age group. Methods We looked at a 10 year study period between 2006 and 2016. Using the hospital's electronic database, we identified outpatient attendances of patients aged between 14 and 16 years. Details of patient demographics, symptomatology, clinic attendances and consultant(s) seen were documented. Results Over our 10-year study period 41 456 patient contacts met the criteria for inclusion, 7 828 (19 %) of these were under direct Paediatric care and 33 628 patients required assistance from other departments. Of the 25 departments offering assistance the most prevalent in order of frequency were Orthopaedics, Otolaryngology, Maxillofacial and Dermatology. Conclusion Our data highlights the demand placed on staff working in Paediatrics upon the extension of the Paediatric age profile. Future work to improve the quality of adolescent outpatient services should emphasize multidisciplinary team work whereby relevant specialties are working together under the leadership of an Adolescent Medicine Physician. Planning for health services is essential to ensure that clinical services are able to meet the current and future needs of the population it serves.

Genetics in Medicine, 2019

Purpose: Haploinsufficiency of DYRK1A causes a recognizable clinical syndrome. The goal of this p... more Purpose: Haploinsufficiency of DYRK1A causes a recognizable clinical syndrome. The goal of this paper is to investigate congenital anomalies of the kidney and urinary tract (CAKUT) and genital defects (GD) in patients with DYRK1A variants. Methods: A large database of clinical exome sequencing (ES) was queried for de novo DYRK1A variants and CAKUT/GD phenotypes were characterized. Xenopus laevis (frog) was chosen as a model organism to assess Dyrk1a's role in renal development. Results: Phenotypic details and variants of 19 patients were compiled after an initial observation that one patient with a de novo pathogenic variant in DYRK1A had GD. CAKUT/GD data were available from 15 patients, 11 of whom presented with CAKUT/GD. Studies in Xenopus embryos demonstrated that knockdown of Dyrk1a, which is expressed in forming nephrons, disrupts the development of segments of embryonic nephrons, which ultimately give rise to the entire genitourinary (GU) tract. These defects could be rescued by coinjecting wild-type human DYRK1A RNA, but not with DYRK1A R205* or DYRK1A L245R RNA. Conclusion: Evidence supports routine GU screening of all individuals with de novo DYRK1A pathogenic variants to ensure optimized clinical management. Collectively, the reported clinical data and loss-of-function studies in Xenopus substantiate a novel role for DYRK1A in GU development.

Journal of Genetic Counseling, 2019

The purpose of this study was to describe current genetic counseling practice in the United State... more The purpose of this study was to describe current genetic counseling practice in the United States following a non‐invasive prenatal testing (NIPT) result positive for a sex chromosome abnormality (SCA). Screening for SCAs can be confounded by confined placental mosaicism, natural loss of the X chromosome from maternal cells during aging, and undiagnosed maternal SCA or copy number variant (CNV). Furthermore, with the exception of 45,X, individuals with SCAs usually have no ultrasound or postnatal findings. This makes follow‐up for unresolved positive NIPT necessary; however, there are currently no clinical guidelines. This study used a cross‐sectional design with an anonymous questionnaire to survey 176 genetic counselors. The majority of prenatal respondents always offered diagnostic testing (>88%) and anatomy ultrasound (~90%), but the percent consistently offering maternal karyotype (22%–52%) and postnatal evaluation (28%–87%) varied. Maternal karyotype was offered more often...

Prenatal Diagnosis, 2019

ObjectiveWe evaluated what prenatal genetic counselor's (GCs) practices, attitudes, and barri... more ObjectiveWe evaluated what prenatal genetic counselor's (GCs) practices, attitudes, and barriers are in regards to prenatal microarray since the publication of the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal‐Fetal Medicine (SMFM) guidelines for microarray use.MethodsThis was a survey‐based cross‐sectional study of English‐speaking, board certified or eligible GCs who currently practice prenatal genetic counseling.ResultsOf 192 respondents, 183 (95%) have incorporated chromosome microarray (CMA) into clinical practice, with 64% believing that the benefits of CMA outweigh the harms and 52% agreeing that CMA should be offered to all women regardless of indication. Those who reported being experts/comfortable in their knowledge of CMA (85%) and familiar with current clinical guidelines (86%) were significantly more likely to offer CMA to patients undergoing invasive testing and patients with fetal anomalies. Patient‐specific concerns were ...

Neuro-Oncology, 2018

NEURO-ONCOLOGY • NOVEMBER 2018 of expression of SMARCAL1 in SMARCAL1-null cell lines markedly sup... more NEURO-ONCOLOGY • NOVEMBER 2018 of expression of SMARCAL1 in SMARCAL1-null cell lines markedly suppressed ALT features and was dependent on the enzyme helicase activity. Furthermore, using break-apart FISH and whole genome sequencing, we identified recurrent rearrangements upstream of TERT in ~50% of triplenegative GBMs. These TERT-rearranged tumors exhibited elevated levels of TERT mRNA expression. This represents a novel mechanism of telomerase activation in GBMs lacking the well-known TERT promoter hotspot mutations. Finally, we identify recurrent BRAF V600E mutations in younger patients with GBM. Collectively, our findings define novel molecular subgroups of glioblastoma, including a telomerase-positive subgroup driven by TERT-structural rearrangements (IDH WT-TERT SV , ~50%), and an ALTpositive subgroup (IDH WT-ALT, ~40%) with mutations in ATRX or SMAR-CAL1. We also establish SMARCAL1 inactivating mutations as a novel genetic mechanism of ALT in cancer.

Advances in chronic kidney disease, 2017

Hypertension (HT) is a public health problem in children particularly related to the epidemic of ... more Hypertension (HT) is a public health problem in children particularly related to the epidemic of overweight and obesity. Monogenic forms of HT are important in the differential diagnosis in children presenting with severe or refractory HT, who have a family history of early-onset HT, unusual physical examination findings, and/or characteristic hormonal and biochemical abnormalities. Most genetic defects in these disorders ultimately result in increased sodium transport in the distal nephron resulting in volume expansion and HT. Genetic testing, which is increasingly available, has diagnostic, therapeutic, and predictive implications for families affected by these rare conditions.

European journal of medical genetics, 2017

Marshall-Smith Syndrome (MRSHSS) is a very rare genetic disorder characterized by failure to thri... more Marshall-Smith Syndrome (MRSHSS) is a very rare genetic disorder characterized by failure to thrive and characteristic dysmorphic features associated with accelerated osseous maturation. We present a nine-year-old girl who was diagnosed with MRSHSS based on characteristic clinical features supported by the identification of a novel de novo pathogenic variant in the NFIX gene. The patient also presented with precocious puberty diagnosed at five years of age and had an abnormal GnRH stimulation test indicative of central precocious puberty. Central precocious puberty has not been described in association with MRSHSS previously in the medical literature and broadens our knowledge of the natural history of MRSHSS. The causes of advanced bone age in this syndrome are also reviewed. Additionally, the patient showed progressive dilatation of the aortic root. Although connective tissue abnormalities have been described in association with MRSHSS, aortic root dilatation has not. Understandin...

American journal of human genetics, 2017

Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in norma... more Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer...

Journal of Pediatric Endocrinology and Metabolism, 2016

Permanent neonatal diabetes (PNDM) is a rare genetic condition characterized by hyperglycemia, in... more Permanent neonatal diabetes (PNDM) is a rare genetic condition characterized by hyperglycemia, insulinopenia, and failure to thrive beginning in the first 6 months of life. Recessive mutations in