Trisomy 16 is the most common autosomal trisomy found in spontaneous abortions with mosaic versio... more Trisomy 16 is the most common autosomal trisomy found in spontaneous abortions with mosaic versions seen in survivors. However, surviving children have multiple congenital defects and are at risk of growth and developmental delay. We report an additional case of mosaic trisomy 16 diagnosed by amniocentesis and confirmed after birth. Our patient is the first documented case of living mosaic trisomy 16 with the malformation constellation of lung agenesis, left pulmonary artery agenesis, congenital heart defects, and ipsilateral radial ray and limb abnormalities, expanding the phenotype of this rare condition. Additionally, this individual's unique combination of lung and cardiac defects caused morbidities that were challenging to manage and complicated family counseling as well.
Background: KMT2B-related dystonia is a primarily childhood-onset movement disorder characterized... more Background: KMT2B-related dystonia is a primarily childhood-onset movement disorder characterized by progressive dystonia, spasticity, and developmental delay. A minority of individuals possess an inherited KMT2B variant. Case Report: As a child, the proband experienced mild developmental delay and laryngeal dystonia which progressed to generalized dystonia. Patellar hyperreflexia, postural tremor, and everted gait were documented. Whole exome sequencing identified a heterozygous pathogenic KMT2B variant in the proband, proband’s sister, and proband’s mother who had milder presentations. Discussion: This novel KMT2B variant reflects intrafamilial variable expressivity in KMT2B-related dystonia. Further identification of variants will allow for better appreciation of the phenotypic spectrum.
Utility and limitations of exome sequencing as a genetic diagnostic to of sequencing and coverage... more Utility and limitations of exome sequencing as a genetic diagnostic to of sequencing and coverage of targeted SCA/D genes and not for primary diagnosis, all patients who had SCA/D (known ed on our lecular erspectives.
Introduction: Sudden cardiac arrest/death (SCA/D) is an uncommon, but tragic occurrence in youth.... more Introduction: Sudden cardiac arrest/death (SCA/D) is an uncommon, but tragic occurrence in youth. Causes include inherited structural, functional, and electrical cardiac abnormalities, with more than 100 known associated genes. A proactive family screening approach is important to provide life-saving treatment and to help identify other affected members due to the high association of genetic causes. Hypothesis: Exome sequencing (ES) can be used to identify genetic causes of SCA/D. Methods: Our objective was to use ES to identify definite and potential causes in families affected with SCA/D. Our study population included 41 probands with clinical symptoms or signs ± family history of SCA/D or SCA/D-associated conditions (affected), but without known molecular etiologies for SCA/D. Additional samples were obtained from 127 family members (parents/siblings/grandparents: 40 clinically affected and 87 unaffected). Samples were analyzed following exome capture and sequencing at an average...
Trisomy 9 mosaic syndrome (T9M) is a rare condition characterized by multiorgan system involvemen... more Trisomy 9 mosaic syndrome (T9M) is a rare condition characterized by multiorgan system involvement including craniofacial dysmorphisms, cardiac, genitourinary (GU), skeletal, and central nervous system (CNS) abnormalities. Although more than 100 cases have been reported in the literature, a comprehensive review has not been performed nor have clinical guidelines been established. Therefore, we describe the clinical features of 16 additional patients, review features of previously reported individuals, and suggest clinical guidelines. Our findings expand the clinical phenotype of T9M, including novel features of amblyopia, astigmatism, corectopia of pupil, posterior embryotoxon, and diaphragmatic eventration. Most patients had prenatal and perinatal issues, particularly from respiratory, growth, and feeding standpoints. Although small birth parameters were common, long‐term growth trends varied widely. An association with advanced parental ages was also identified. The spectrum of gr...
Background and ObjectivesPurine-rich element-binding protein A (PURA) gene encodes Pur-α, a conse... more Background and ObjectivesPurine-rich element-binding protein A (PURA) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients.MethodsData on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained.ResultsA cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epil...
Preimplantation genetic testing for monogenic disorders (PGT‐M) was originally developed to ident... more Preimplantation genetic testing for monogenic disorders (PGT‐M) was originally developed to identify embryos affected with serious childhood‐onset disorders, but its use has recently broadened. Guidance on the use of PGT‐M in the United States (U.S.) is currently limited, with no formal laws or guidelines established on its use. The goals of this study were to determine for which types of conditions U.S. laboratories currently do not offer PGT‐M, to explore ethical considerations U.S. laboratory genetic counselors (GCs) take into consideration when deciding to accept or reject a PGT‐M request, and to explore whether U.S. laboratory GCs believe PGT‐M should be offered for conditions with reduced penetrance or for variants of uncertain significance (VUS). Qualitative analysis of semi‐structured interviews with nine genetic counselors, from five different PGT‐M laboratories, was conducted. Participants were required to be GCs working at a PGT‐M laboratory in the U.S. and either activel...
We report the first case of a 294 kb loss, notable for including the entirety of GPD1L, on chromo... more We report the first case of a 294 kb loss, notable for including the entirety of GPD1L, on chromosome 3p22.3—p24 in a 3-year-old girl with multiple congenital anomalies including absent left foot, single umbilical artery, bilateral vesico-ureteral reflux, rectovaginal fistula, and imperforate anus. Although GPD1L mutations have been associated with cardiac arrhythmias, including Brugada syndrome and sudden unexpected infant death syndrome, full deletions in the GPD1L gene have not been reported neither the patient nor her mother, who was later identified to carry the variant, have any signs or symptoms of Brugada syndrome. This may indicate these individuals have findings that have not yet been identified, full gene deletions of GDP1L are not necessarily disease causing, or there is incomplete penetrance of this gene or cardiac manifestations can occur at a later age.
Lysosomal storage diseases (LSDs) are a heterogeneous group of genetic disorders caused by defect... more Lysosomal storage diseases (LSDs) are a heterogeneous group of genetic disorders caused by defects in lysosomal function that lead to multiorgan system damage. Due to wide clinical variability within even a single disorder, making a diagnosis can be difficult and identification may be delayed. Enzyme replacement therapy (ERT) was first approved as a treatment for the LSD Gaucher disease in 1991. ERT development for other LSDs followed, and ERT is currently approved for eight LSDs in the United States. ERT may help slow progression and improve clinical symptoms, but it cannot affect neurologic features due to its inability to cross the blood-brain barrier. Additional therapies for LSDs that have been investigated include stem cell transplants, gene therapy, small molecule approaches, and genome editing. Although newer approaches seem promising, there is no “cure” for any LSDs, and management remains focused on early diagnosis and treatment. [ Pediatr Ann. 2018;47(5):e191–e197.]
Conditions associated with sudden cardiac arrest/death (SCA/D) in youth often have a genetic etio... more Conditions associated with sudden cardiac arrest/death (SCA/D) in youth often have a genetic etiology. While SCA/D is uncommon, a pro-active family screening approach may identify these inherited structural and electrical abnormalities prior to symptomatic events and allow appropriate surveillance and treatment. This study investigated the diagnostic utility of exome sequencing (ES) by evaluating the capture and coverage of genes related to SCA/D. Samples from 102 individuals (13 with known molecular etiologies for SCA/D, 30 individuals without known molecular etiologies for SCA/D and 59 with other conditions) were analyzed following exome capture and sequencing at an average read depth of 100X. Reads were mapped to human genome GRCh37 using Novoalign, and post-processing and analysis was done using Picard and GATK. A total of 103 genes (2,190 exons) related to SCA/D were used as a primary filter. An additional 100 random variants within the targeted genes associated with SCA/D were...
Trisomy 16 is the most common autosomal trisomy found in spontaneous abortions with mosaic versio... more Trisomy 16 is the most common autosomal trisomy found in spontaneous abortions with mosaic versions seen in survivors. However, surviving children have multiple congenital defects and are at risk of growth and developmental delay. We report an additional case of mosaic trisomy 16 diagnosed by amniocentesis and confirmed after birth. Our patient is the first documented case of living mosaic trisomy 16 with the malformation constellation of lung agenesis, left pulmonary artery agenesis, congenital heart defects, and ipsilateral radial ray and limb abnormalities, expanding the phenotype of this rare condition. Additionally, this individual's unique combination of lung and cardiac defects caused morbidities that were challenging to manage and complicated family counseling as well.
Background: KMT2B-related dystonia is a primarily childhood-onset movement disorder characterized... more Background: KMT2B-related dystonia is a primarily childhood-onset movement disorder characterized by progressive dystonia, spasticity, and developmental delay. A minority of individuals possess an inherited KMT2B variant. Case Report: As a child, the proband experienced mild developmental delay and laryngeal dystonia which progressed to generalized dystonia. Patellar hyperreflexia, postural tremor, and everted gait were documented. Whole exome sequencing identified a heterozygous pathogenic KMT2B variant in the proband, proband’s sister, and proband’s mother who had milder presentations. Discussion: This novel KMT2B variant reflects intrafamilial variable expressivity in KMT2B-related dystonia. Further identification of variants will allow for better appreciation of the phenotypic spectrum.
Utility and limitations of exome sequencing as a genetic diagnostic to of sequencing and coverage... more Utility and limitations of exome sequencing as a genetic diagnostic to of sequencing and coverage of targeted SCA/D genes and not for primary diagnosis, all patients who had SCA/D (known ed on our lecular erspectives.
Introduction: Sudden cardiac arrest/death (SCA/D) is an uncommon, but tragic occurrence in youth.... more Introduction: Sudden cardiac arrest/death (SCA/D) is an uncommon, but tragic occurrence in youth. Causes include inherited structural, functional, and electrical cardiac abnormalities, with more than 100 known associated genes. A proactive family screening approach is important to provide life-saving treatment and to help identify other affected members due to the high association of genetic causes. Hypothesis: Exome sequencing (ES) can be used to identify genetic causes of SCA/D. Methods: Our objective was to use ES to identify definite and potential causes in families affected with SCA/D. Our study population included 41 probands with clinical symptoms or signs ± family history of SCA/D or SCA/D-associated conditions (affected), but without known molecular etiologies for SCA/D. Additional samples were obtained from 127 family members (parents/siblings/grandparents: 40 clinically affected and 87 unaffected). Samples were analyzed following exome capture and sequencing at an average...
Trisomy 9 mosaic syndrome (T9M) is a rare condition characterized by multiorgan system involvemen... more Trisomy 9 mosaic syndrome (T9M) is a rare condition characterized by multiorgan system involvement including craniofacial dysmorphisms, cardiac, genitourinary (GU), skeletal, and central nervous system (CNS) abnormalities. Although more than 100 cases have been reported in the literature, a comprehensive review has not been performed nor have clinical guidelines been established. Therefore, we describe the clinical features of 16 additional patients, review features of previously reported individuals, and suggest clinical guidelines. Our findings expand the clinical phenotype of T9M, including novel features of amblyopia, astigmatism, corectopia of pupil, posterior embryotoxon, and diaphragmatic eventration. Most patients had prenatal and perinatal issues, particularly from respiratory, growth, and feeding standpoints. Although small birth parameters were common, long‐term growth trends varied widely. An association with advanced parental ages was also identified. The spectrum of gr...
Background and ObjectivesPurine-rich element-binding protein A (PURA) gene encodes Pur-α, a conse... more Background and ObjectivesPurine-rich element-binding protein A (PURA) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients.MethodsData on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained.ResultsA cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epil...
Preimplantation genetic testing for monogenic disorders (PGT‐M) was originally developed to ident... more Preimplantation genetic testing for monogenic disorders (PGT‐M) was originally developed to identify embryos affected with serious childhood‐onset disorders, but its use has recently broadened. Guidance on the use of PGT‐M in the United States (U.S.) is currently limited, with no formal laws or guidelines established on its use. The goals of this study were to determine for which types of conditions U.S. laboratories currently do not offer PGT‐M, to explore ethical considerations U.S. laboratory genetic counselors (GCs) take into consideration when deciding to accept or reject a PGT‐M request, and to explore whether U.S. laboratory GCs believe PGT‐M should be offered for conditions with reduced penetrance or for variants of uncertain significance (VUS). Qualitative analysis of semi‐structured interviews with nine genetic counselors, from five different PGT‐M laboratories, was conducted. Participants were required to be GCs working at a PGT‐M laboratory in the U.S. and either activel...
We report the first case of a 294 kb loss, notable for including the entirety of GPD1L, on chromo... more We report the first case of a 294 kb loss, notable for including the entirety of GPD1L, on chromosome 3p22.3—p24 in a 3-year-old girl with multiple congenital anomalies including absent left foot, single umbilical artery, bilateral vesico-ureteral reflux, rectovaginal fistula, and imperforate anus. Although GPD1L mutations have been associated with cardiac arrhythmias, including Brugada syndrome and sudden unexpected infant death syndrome, full deletions in the GPD1L gene have not been reported neither the patient nor her mother, who was later identified to carry the variant, have any signs or symptoms of Brugada syndrome. This may indicate these individuals have findings that have not yet been identified, full gene deletions of GDP1L are not necessarily disease causing, or there is incomplete penetrance of this gene or cardiac manifestations can occur at a later age.
Lysosomal storage diseases (LSDs) are a heterogeneous group of genetic disorders caused by defect... more Lysosomal storage diseases (LSDs) are a heterogeneous group of genetic disorders caused by defects in lysosomal function that lead to multiorgan system damage. Due to wide clinical variability within even a single disorder, making a diagnosis can be difficult and identification may be delayed. Enzyme replacement therapy (ERT) was first approved as a treatment for the LSD Gaucher disease in 1991. ERT development for other LSDs followed, and ERT is currently approved for eight LSDs in the United States. ERT may help slow progression and improve clinical symptoms, but it cannot affect neurologic features due to its inability to cross the blood-brain barrier. Additional therapies for LSDs that have been investigated include stem cell transplants, gene therapy, small molecule approaches, and genome editing. Although newer approaches seem promising, there is no “cure” for any LSDs, and management remains focused on early diagnosis and treatment. [ Pediatr Ann. 2018;47(5):e191–e197.]
Conditions associated with sudden cardiac arrest/death (SCA/D) in youth often have a genetic etio... more Conditions associated with sudden cardiac arrest/death (SCA/D) in youth often have a genetic etiology. While SCA/D is uncommon, a pro-active family screening approach may identify these inherited structural and electrical abnormalities prior to symptomatic events and allow appropriate surveillance and treatment. This study investigated the diagnostic utility of exome sequencing (ES) by evaluating the capture and coverage of genes related to SCA/D. Samples from 102 individuals (13 with known molecular etiologies for SCA/D, 30 individuals without known molecular etiologies for SCA/D and 59 with other conditions) were analyzed following exome capture and sequencing at an average read depth of 100X. Reads were mapped to human genome GRCh37 using Novoalign, and post-processing and analysis was done using Picard and GATK. A total of 103 genes (2,190 exons) related to SCA/D were used as a primary filter. An additional 100 random variants within the targeted genes associated with SCA/D were...
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