Children with Down syndrome (DS) have increased risk for multiple medical conditions with publish... more Children with Down syndrome (DS) have increased risk for multiple medical conditions with published health care guidelines. Current guidelines do not specify whether or not they apply to mosaic DS (mDS). We surveyed families of patients with mDS regarding screening, including monitoring practices as well as complications identified. Hematological complications were similar to those reported in nonmosaic DS. Of 91 parents of children with mDS surveyed, only 69% had ever had a screening lab; only 57% had ever had a screening complete blood count (CBC). Younger children were less likely to be screened (for CBC, 50% of 0- to 3-year-olds vs 90% of 4- to 12-year-olds; P = 0.0036). Screening practices are suboptimal, with the youngest children at greatest risk. Comparing reported screening practices with physician adherence, there was discrepancy between perceptions of adherence and perceptions of practice. Children with mDS should be monitored on the same schedule as other children with DS.
Mutations in the type XI collagen alpha-1 chain gene (COL11A1) cause a change in protein structur... more Mutations in the type XI collagen alpha-1 chain gene (COL11A1) cause a change in protein structure that alters its interactions with collagens II and V, resulting in abnormalities in cartilage and ocular vitreous. The most common type XI collagenopathies are dominantly inherited Stickler or Marshall syndromes, while severe recessive skeletal dysplasias, such as fibrochondrogenesis, occur less frequently. We describe a family with a severe skeletal dysplasia caused by a novel dominantly inherited COL11A1 mutation. The siblings each presented with severe myopia, hearing loss, micromelia, metaphyseal widening of the long bones, micrognathia and airway compromise requiring tracheostomy. The first child lived for over 2 years, while the second succumbed at 5 months of age. Their mother has mild rhizomelic shortening of the limbs, brachydactyly, and severe myopia. Sequencing of COL11A1 revealed a novel deleterious heterozygous mutation in COL11A1 involving the triple helical domain in both siblings, and a mosaic mutation in their mother, indicating germline mosaicism with subsequent dominant inheritance. These are the first reported individuals with a dominantly inherited mutation in COL11A1 associated with a severe skeletal dysplasia. The skeletal involvement is similar to, yet milder than fibrochondrogenesis and allowed for survival beyond the perinatal period. These cases highlight both a novel dominant COL11A1 mutation causing a significant skeletal dysplasia and the phenotypic heterogeneity of collagenopathies.
American Journal of Medical Genetics, May 10, 2021
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 growth and development was wide, ranging from nonverbal patients to those able to participate in educational programs with age-appropriate peers. The severity of clinical outcomes was unrelated to blood lymphocyte mosaicism levels. Microarray analysis had a higher diagnostic rate compared to standard karyotype analysis and should be utilized if this diagnosis is suspected. Future longitudinal studies will be key to monitor long-term outcomes of individuals with T9M and determine best practices for clinical management.
Cleidocranial dysplasia (CCD) is an autosomal-dominant skeletal dysplasia syndrome that is charac... more Cleidocranial dysplasia (CCD) is an autosomal-dominant skeletal dysplasia syndrome that is characterized by widely patent calvarial sutures, clavicular hypoplasia, supernumerary teeth, and short stature. CCD is caused by mutations in the transcription factor RUNX2, which is known to function as a major regulator of bone differentiation. Despite the characterization of 67 unique mutations in 97 individual cases, and the availability of animal models, no obvious genotype-phenotype correlation has emerged. We describe 3 new cases that were ascertained on the basis of a severe calvarial phenotype, that were associated with 3 novel mutations in the C-terminal region of RUNX2 distal to the DNA-binding runt domain. In addition, a review of all previously described cases was undertaken in an effort to standardize mutation nomenclature, characterize the position of known mutations relative to the runt domain, and explore the hypothesis that C-terminal mutations that preserve the runt domain may lead to more-severe craniofacial phenotypes. Upon mutational analysis of RUNX2, we identified either frameshift or splice-site mutations that affect the C-terminal region of the resultant protein distal to the runt domain. In the context of previously described mutations, these cases suggest that C-terminal mutations that preserve the DNA-binding runt domain while disrupting the SMAD 1,2,3,5 binding domain and the nuclear matrix targeting signal may be responsible for the severe phenotype observed.
American Journal of Medical Genetics, Sep 27, 2021
Robin sequence (RS), the triad of micrognathia, glossoptosis, and airway obstruction, is a major ... more Robin sequence (RS), the triad of micrognathia, glossoptosis, and airway obstruction, is a major cause of respiratory distress and feeding difficulties in neonates. Robin sequence can be associated with other medical or developmental comorbidities in ~50% of cases (“syndromic” RS). As well, RS is variably associated with cleft palate (CP). Previous studies have not investigated differences in clinical characteristics of children with RS based on presence or absence of CP. We retrospectively reviewed 175 children with RS and compared genetic diagnoses, medical and developmental comorbidities, severity of airway obstruction, and feeding outcomes between those with and without CP. Strikingly, 45 of 45 (100%) children with RS without CP were classified as syndromic due to presence of comorbidities unrelated to RS, while 83 of 130 (64%) children with RS with CP were classified as syndromic. Among 128 children with syndromic RS, there were no differences in severity of airway obstruction, surgical intervention rate or type, or feeding outcome at 12 months based on CP status. Our findings support the conclusion that the pathogenesis of RS without CP is distinct from RS with CP and more likely to cause additional medical or developmental problems. Alternatively, children with RS without CP and without additional anomalies present may be under recognized.
BackgroundDefects in the RYR1 (OMIM#180901) gene lead to Ryanodine receptor type 1‐related myopat... more BackgroundDefects in the RYR1 (OMIM#180901) gene lead to Ryanodine receptor type 1‐related myopathies (RYR1‐RM); the most common subgroup of congenital myopathies.MethodsCongenital myopathy presents a diagnostic challenge due to the need for multiple testing modalities to identify the many different genetic etiologies. In this case, the patient remained undiagnosed after whole‐exome sequencing (WES), chromosomal microarray, methylation analysis, targeted deletion and duplication studies, and targeted repeat expansion studies. Clinical whole‐genome sequencing (WGS) was then pursued as part of a research study to identify a diagnosis.ResultsWGS identified compound heterozygous RYR1 intronic variants, RNA sequencing confirmed both variants to be pathogenic causing RYR1‐RM in a phenotype of severe congenital hypotonia with respiratory failure from birth, neonatal brain hemorrhage, and congenital heart disease involving transposition of the great arteries.ConclusionWhile there is an ongoing debate about the clinical superiority of WGS versus WES for patients with a suspected genetic condition, this scenario highlights a weakness of WES as well as the added cost and delay in diagnosis timing with having WGS follow WES or even ending further genetic testing with a negative WES. While knowledge gaps still exist for many intronic variants, transcriptome analysis provides a way of validating the resulting dysfunction caused by these variants and thus allowing for appropriate pathogenicity classification. This is the second published case report of a patient with pathogenic intronic variants in RYR1‐RM, with clinical RNA testing confirming variant pathogenicity and therefore the diagnosis suggesting that for some patients careful analysis of a patient's genome and transcriptome are required for a complete genetic evaluation. The diagnostic odyssey experienced by this patient highlights the importance of early, rapid WGS.
Protein phosphatase 2A (PP2A) is a heterotrimeric serine/threonine phosphatase that regulates num... more Protein phosphatase 2A (PP2A) is a heterotrimeric serine/threonine phosphatase that regulates numerous biological processes. PPP2R1A encodes the scaffolding “Aα” subunit of PP2A. To date, nearly 40 patients have been previously reported with 19 different pathogenic PPP2R1A variants, with phenotypes including intellectual disability, developmental delay, epilepsy, infant agenesis/dysgenesis of the corpus callosum, and dysmorphic features. Apart from a single case, severe congenital heart defects (CHD) have not been described. We report four new unrelated individuals with pathogenic heterozygous PPP2R1A variants and CHD and model the crystal structure of several variants to investigate mechanisms of phenotype disparity. Individuals 1 and 2 have a previously described variant (c.548G>A, p.R183Q) and similar phenotypes with severe ventriculomegaly, agenesis/dysgenesis of the corpus callosum, and severe CHD. Individual 3 also has a recurrent variant (c.544C>T, p.R182W) and presente...
Proteus syndrome is a mosaic genetic overgrowth disorder caused by a postzygotic, mosaic activati... more Proteus syndrome is a mosaic genetic overgrowth disorder caused by a postzygotic, mosaic activating mutation in AKT1. Rare prenatal presentations include segmental tissue overgrowth, and skeletal and CNS anomalies. We present the first report of prenatally diagnosed and molecularly confirmed Proteus syndrome. Prenatal imaging identified megalencephaly, brain and eye malformations, focal soft tissue enlargement, and ambiguous genitalia. Exome sequencing performed on cultured amniocytes demonstrated an AKT1 pathogenic variant consistent with Proteus syndrome, and postnatal examination confirmed the diagnosis. Postnatal Sanger sequencing could not identify the AKT1 pathogenic variant. This case underscores the importance of prenatal exome sequencing on cultured amniocytes for mosaic overgrowth disorders, as well as provides additional information on the prenatal phenotype of Proteus syndrome, and highlights the impact of prenatal diagnosis on postnatal management.
Children with Down syndrome (DS) have increased risk for multiple medical conditions with publish... more Children with Down syndrome (DS) have increased risk for multiple medical conditions with published health care guidelines. Current guidelines do not specify whether or not they apply to mosaic DS (mDS). We surveyed families of patients with mDS regarding screening, including monitoring practices as well as complications identified. Hematological complications were similar to those reported in nonmosaic DS. Of 91 parents of children with mDS surveyed, only 69% had ever had a screening lab; only 57% had ever had a screening complete blood count (CBC). Younger children were less likely to be screened (for CBC, 50% of 0- to 3-year-olds vs 90% of 4- to 12-year-olds; P = 0.0036). Screening practices are suboptimal, with the youngest children at greatest risk. Comparing reported screening practices with physician adherence, there was discrepancy between perceptions of adherence and perceptions of practice. Children with mDS should be monitored on the same schedule as other children with DS.
Mutations in the type XI collagen alpha-1 chain gene (COL11A1) cause a change in protein structur... more Mutations in the type XI collagen alpha-1 chain gene (COL11A1) cause a change in protein structure that alters its interactions with collagens II and V, resulting in abnormalities in cartilage and ocular vitreous. The most common type XI collagenopathies are dominantly inherited Stickler or Marshall syndromes, while severe recessive skeletal dysplasias, such as fibrochondrogenesis, occur less frequently. We describe a family with a severe skeletal dysplasia caused by a novel dominantly inherited COL11A1 mutation. The siblings each presented with severe myopia, hearing loss, micromelia, metaphyseal widening of the long bones, micrognathia and airway compromise requiring tracheostomy. The first child lived for over 2 years, while the second succumbed at 5 months of age. Their mother has mild rhizomelic shortening of the limbs, brachydactyly, and severe myopia. Sequencing of COL11A1 revealed a novel deleterious heterozygous mutation in COL11A1 involving the triple helical domain in both siblings, and a mosaic mutation in their mother, indicating germline mosaicism with subsequent dominant inheritance. These are the first reported individuals with a dominantly inherited mutation in COL11A1 associated with a severe skeletal dysplasia. The skeletal involvement is similar to, yet milder than fibrochondrogenesis and allowed for survival beyond the perinatal period. These cases highlight both a novel dominant COL11A1 mutation causing a significant skeletal dysplasia and the phenotypic heterogeneity of collagenopathies.
American Journal of Medical Genetics, May 10, 2021
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 growth and development was wide, ranging from nonverbal patients to those able to participate in educational programs with age-appropriate peers. The severity of clinical outcomes was unrelated to blood lymphocyte mosaicism levels. Microarray analysis had a higher diagnostic rate compared to standard karyotype analysis and should be utilized if this diagnosis is suspected. Future longitudinal studies will be key to monitor long-term outcomes of individuals with T9M and determine best practices for clinical management.
Cleidocranial dysplasia (CCD) is an autosomal-dominant skeletal dysplasia syndrome that is charac... more Cleidocranial dysplasia (CCD) is an autosomal-dominant skeletal dysplasia syndrome that is characterized by widely patent calvarial sutures, clavicular hypoplasia, supernumerary teeth, and short stature. CCD is caused by mutations in the transcription factor RUNX2, which is known to function as a major regulator of bone differentiation. Despite the characterization of 67 unique mutations in 97 individual cases, and the availability of animal models, no obvious genotype-phenotype correlation has emerged. We describe 3 new cases that were ascertained on the basis of a severe calvarial phenotype, that were associated with 3 novel mutations in the C-terminal region of RUNX2 distal to the DNA-binding runt domain. In addition, a review of all previously described cases was undertaken in an effort to standardize mutation nomenclature, characterize the position of known mutations relative to the runt domain, and explore the hypothesis that C-terminal mutations that preserve the runt domain may lead to more-severe craniofacial phenotypes. Upon mutational analysis of RUNX2, we identified either frameshift or splice-site mutations that affect the C-terminal region of the resultant protein distal to the runt domain. In the context of previously described mutations, these cases suggest that C-terminal mutations that preserve the DNA-binding runt domain while disrupting the SMAD 1,2,3,5 binding domain and the nuclear matrix targeting signal may be responsible for the severe phenotype observed.
American Journal of Medical Genetics, Sep 27, 2021
Robin sequence (RS), the triad of micrognathia, glossoptosis, and airway obstruction, is a major ... more Robin sequence (RS), the triad of micrognathia, glossoptosis, and airway obstruction, is a major cause of respiratory distress and feeding difficulties in neonates. Robin sequence can be associated with other medical or developmental comorbidities in ~50% of cases (“syndromic” RS). As well, RS is variably associated with cleft palate (CP). Previous studies have not investigated differences in clinical characteristics of children with RS based on presence or absence of CP. We retrospectively reviewed 175 children with RS and compared genetic diagnoses, medical and developmental comorbidities, severity of airway obstruction, and feeding outcomes between those with and without CP. Strikingly, 45 of 45 (100%) children with RS without CP were classified as syndromic due to presence of comorbidities unrelated to RS, while 83 of 130 (64%) children with RS with CP were classified as syndromic. Among 128 children with syndromic RS, there were no differences in severity of airway obstruction, surgical intervention rate or type, or feeding outcome at 12 months based on CP status. Our findings support the conclusion that the pathogenesis of RS without CP is distinct from RS with CP and more likely to cause additional medical or developmental problems. Alternatively, children with RS without CP and without additional anomalies present may be under recognized.
BackgroundDefects in the RYR1 (OMIM#180901) gene lead to Ryanodine receptor type 1‐related myopat... more BackgroundDefects in the RYR1 (OMIM#180901) gene lead to Ryanodine receptor type 1‐related myopathies (RYR1‐RM); the most common subgroup of congenital myopathies.MethodsCongenital myopathy presents a diagnostic challenge due to the need for multiple testing modalities to identify the many different genetic etiologies. In this case, the patient remained undiagnosed after whole‐exome sequencing (WES), chromosomal microarray, methylation analysis, targeted deletion and duplication studies, and targeted repeat expansion studies. Clinical whole‐genome sequencing (WGS) was then pursued as part of a research study to identify a diagnosis.ResultsWGS identified compound heterozygous RYR1 intronic variants, RNA sequencing confirmed both variants to be pathogenic causing RYR1‐RM in a phenotype of severe congenital hypotonia with respiratory failure from birth, neonatal brain hemorrhage, and congenital heart disease involving transposition of the great arteries.ConclusionWhile there is an ongoing debate about the clinical superiority of WGS versus WES for patients with a suspected genetic condition, this scenario highlights a weakness of WES as well as the added cost and delay in diagnosis timing with having WGS follow WES or even ending further genetic testing with a negative WES. While knowledge gaps still exist for many intronic variants, transcriptome analysis provides a way of validating the resulting dysfunction caused by these variants and thus allowing for appropriate pathogenicity classification. This is the second published case report of a patient with pathogenic intronic variants in RYR1‐RM, with clinical RNA testing confirming variant pathogenicity and therefore the diagnosis suggesting that for some patients careful analysis of a patient's genome and transcriptome are required for a complete genetic evaluation. The diagnostic odyssey experienced by this patient highlights the importance of early, rapid WGS.
Protein phosphatase 2A (PP2A) is a heterotrimeric serine/threonine phosphatase that regulates num... more Protein phosphatase 2A (PP2A) is a heterotrimeric serine/threonine phosphatase that regulates numerous biological processes. PPP2R1A encodes the scaffolding “Aα” subunit of PP2A. To date, nearly 40 patients have been previously reported with 19 different pathogenic PPP2R1A variants, with phenotypes including intellectual disability, developmental delay, epilepsy, infant agenesis/dysgenesis of the corpus callosum, and dysmorphic features. Apart from a single case, severe congenital heart defects (CHD) have not been described. We report four new unrelated individuals with pathogenic heterozygous PPP2R1A variants and CHD and model the crystal structure of several variants to investigate mechanisms of phenotype disparity. Individuals 1 and 2 have a previously described variant (c.548G>A, p.R183Q) and similar phenotypes with severe ventriculomegaly, agenesis/dysgenesis of the corpus callosum, and severe CHD. Individual 3 also has a recurrent variant (c.544C>T, p.R182W) and presente...
Proteus syndrome is a mosaic genetic overgrowth disorder caused by a postzygotic, mosaic activati... more Proteus syndrome is a mosaic genetic overgrowth disorder caused by a postzygotic, mosaic activating mutation in AKT1. Rare prenatal presentations include segmental tissue overgrowth, and skeletal and CNS anomalies. We present the first report of prenatally diagnosed and molecularly confirmed Proteus syndrome. Prenatal imaging identified megalencephaly, brain and eye malformations, focal soft tissue enlargement, and ambiguous genitalia. Exome sequencing performed on cultured amniocytes demonstrated an AKT1 pathogenic variant consistent with Proteus syndrome, and postnatal examination confirmed the diagnosis. Postnatal Sanger sequencing could not identify the AKT1 pathogenic variant. This case underscores the importance of prenatal exome sequencing on cultured amniocytes for mosaic overgrowth disorders, as well as provides additional information on the prenatal phenotype of Proteus syndrome, and highlights the impact of prenatal diagnosis on postnatal management.
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Papers by Robert J Hopkin