Ryan J German, Blake Vuocolo, Liesbeth Vossaert, Lisa Saba, Robin Fletcher, Matthew L Tedder, Bekim Sadikovic, Jennifer Kerkhof, Michael Wangler, Carlos A Bacino
We report a 40-year-old African American female with a novel variant in exon 8 of DNA methyltransferase 3 alpha (DNMT3A), (NM_022552.4: c.905G>C, p.G302A) who presented with a history of recurrent carotid paragangliomas, mediastinal mass, intellectual disability, dysarthria, cholelithiasis, diabetes mellitus, hypertension, and dysmorphic features. We interpret this novel variant as likely pathogenic and causative for the patient's syndromic features of Heyn-Sproul-Jackson syndrome. Heyn-Sproul-Jackson syndrome is a condition caused by gain-of-function genetic changes in DNMT3A. Paragangliomas have also been observed in non-syndromic patients with genetic alterations in DNMT3A. We describe a patient with clinical features of Heyn-Sproul-Jackson syndrome such as intellectual disability, dysarthria, brachydactyly, and lack of brain MRI findings to add evidence to associate paragangliomas with DNMT3A and draw particular attention to the potential involvement of the proline-tryptophan-tryptophan-proline domain of DNMT3A.
{"title":"Recurrent carotid paragangliomas in a syndromic patient with a heterozygous missense variant in DNA Methyltransferase 3 Alpha.","authors":"Ryan J German, Blake Vuocolo, Liesbeth Vossaert, Lisa Saba, Robin Fletcher, Matthew L Tedder, Bekim Sadikovic, Jennifer Kerkhof, Michael Wangler, Carlos A Bacino","doi":"10.1002/ajmg.a.63849","DOIUrl":"10.1002/ajmg.a.63849","url":null,"abstract":"<p><p>We report a 40-year-old African American female with a novel variant in exon 8 of DNA methyltransferase 3 alpha (DNMT3A), (NM_022552.4: c.905G>C, p.G302A) who presented with a history of recurrent carotid paragangliomas, mediastinal mass, intellectual disability, dysarthria, cholelithiasis, diabetes mellitus, hypertension, and dysmorphic features. We interpret this novel variant as likely pathogenic and causative for the patient's syndromic features of Heyn-Sproul-Jackson syndrome. Heyn-Sproul-Jackson syndrome is a condition caused by gain-of-function genetic changes in DNMT3A. Paragangliomas have also been observed in non-syndromic patients with genetic alterations in DNMT3A. We describe a patient with clinical features of Heyn-Sproul-Jackson syndrome such as intellectual disability, dysarthria, brachydactyly, and lack of brain MRI findings to add evidence to associate paragangliomas with DNMT3A and draw particular attention to the potential involvement of the proline-tryptophan-tryptophan-proline domain of DNMT3A.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mia O'Connell, Elizabeth Harstad, Jennifer Aites, Katheryn Hayes, Anne B Arnett, Julia Scotellaro, Soleha Patel, Stephanie J Brewster, William Barbaresi, Ryan N Doan
Attention-deficit/hyperactivity disorder (ADHD) belongs to a phenotypically broad class of mental health disorders impacting social and cognitive functioning. Despite heritability estimates of 77%-88% and a global prevalence of up to 1 in 20 children, most of the underlying genetic etiology of the disorder remains undiscovered, making it challenging to obtain a clinical molecular genetic diagnosis and to develop new treatments (Biological Psychiatry, 2005, 57, 1313; Psychological Bulletin, 2009, 135, 608; Psychological Medicine, 2014, 44, 2223). Here we report the identification of a novel ultra-rare heterozygous loss-of-function (p.Q1625*) variant in a child with complex ADHD (i.e., comorbid mild intellectual disability [ID]) and a missense (p.G1748R) variant (allele frequency of 4.7 × 10-5) in a child with primary ADHD (i.e., absence of comorbid autism spectrum disorder [ASD], ID, or syndromic features) both in the SPTBN1 gene. Missense variants in SPTBN1 have been reported in individuals with developmental disorders, language and communication disorders, and motor delays in recent publications (Nature Genetics, 2021, 53, 1006; American Journal of Medical Genetics Part A, 2021, 185, 2037) and ClinVar, though most variants in ClinVar have uncertain disease associations. The functional impact of these 135 variants, including from the current study, were further assessed using prediction scores from the recently developed AlphaMissense tool and benchmarked against published functional studies on a subset of the variants. While heterozygous SPTBN1 variants have recently been associated with neurodevelopmental disorders characterized by global developmental delay, intellectual disability, and behavioral abnormalities, the two patients in the current study expand the phenotypic spectrum to include ADHD in the absence of more severe neurodevelopmental disorders, such as ASD and moderate to severe ID. Furthermore, the culmination of these data with existing reported cases suggests that variation including loss of function and missense events underlie a broader clinical spectrum than previously understood.
{"title":"Diverse clinical presentation of SPTBN1 variants: Complex versus primary attention-deficit/hyperactivity disorder.","authors":"Mia O'Connell, Elizabeth Harstad, Jennifer Aites, Katheryn Hayes, Anne B Arnett, Julia Scotellaro, Soleha Patel, Stephanie J Brewster, William Barbaresi, Ryan N Doan","doi":"10.1002/ajmg.a.63851","DOIUrl":"https://doi.org/10.1002/ajmg.a.63851","url":null,"abstract":"<p><p>Attention-deficit/hyperactivity disorder (ADHD) belongs to a phenotypically broad class of mental health disorders impacting social and cognitive functioning. Despite heritability estimates of 77%-88% and a global prevalence of up to 1 in 20 children, most of the underlying genetic etiology of the disorder remains undiscovered, making it challenging to obtain a clinical molecular genetic diagnosis and to develop new treatments (Biological Psychiatry, 2005, 57, 1313; Psychological Bulletin, 2009, 135, 608; Psychological Medicine, 2014, 44, 2223). Here we report the identification of a novel ultra-rare heterozygous loss-of-function (p.Q1625*) variant in a child with complex ADHD (i.e., comorbid mild intellectual disability [ID]) and a missense (p.G1748R) variant (allele frequency of 4.7 × 10<sup>-5</sup>) in a child with primary ADHD (i.e., absence of comorbid autism spectrum disorder [ASD], ID, or syndromic features) both in the SPTBN1 gene. Missense variants in SPTBN1 have been reported in individuals with developmental disorders, language and communication disorders, and motor delays in recent publications (Nature Genetics, 2021, 53, 1006; American Journal of Medical Genetics Part A, 2021, 185, 2037) and ClinVar, though most variants in ClinVar have uncertain disease associations. The functional impact of these 135 variants, including from the current study, were further assessed using prediction scores from the recently developed AlphaMissense tool and benchmarked against published functional studies on a subset of the variants. While heterozygous SPTBN1 variants have recently been associated with neurodevelopmental disorders characterized by global developmental delay, intellectual disability, and behavioral abnormalities, the two patients in the current study expand the phenotypic spectrum to include ADHD in the absence of more severe neurodevelopmental disorders, such as ASD and moderate to severe ID. Furthermore, the culmination of these data with existing reported cases suggests that variation including loss of function and missense events underlie a broader clinical spectrum than previously understood.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Soo-Jeong Kim, Lydia Kim, Waylon Howard, Bridget McNulty, Parisa Salehi
Prader-Willi syndrome (PWS) is a rare genetic disorder caused by the loss of paternal genes on chromosome 15. The Aberrant Behavior Checklist (ABC) is a standardized rating scale for assessing problematic behaviors in persons with developmental disabilities. Our study aims to describe ABC scores in youth with PWS and track their change over time. The analysis included 69 patients. Mean ABC scores were compared in four age groups (5-8, 9-12, 13-16, and 17-22 years). A statistically significant difference was found only in the Irritability subscale, with lower scores in the 5-8 age group compared to the 9-12 age group. For change over time, scores for Irritability, Lethargy, Stereotypic Behavior, Hyperactivity subscales, and Total score were likely to decrease after age 12. Irritability subscale scores of males were predicted to increase more than those of females between ages of 5 and 12 . The Lethargy score in the nondeletion group had a greater reduction than the deletion group in the 12-20 year range. This study highlights the need for systematic collection and characterization of behavioral data given the burden of maladaptive behaviors that often persist for a lifetime.
{"title":"Aberrant behavior checklist in youth with Prader-Willi syndrome: Preliminary study of cross-sectional and longitudinal behavior characterization.","authors":"Soo-Jeong Kim, Lydia Kim, Waylon Howard, Bridget McNulty, Parisa Salehi","doi":"10.1002/ajmg.a.63853","DOIUrl":"https://doi.org/10.1002/ajmg.a.63853","url":null,"abstract":"<p><p>Prader-Willi syndrome (PWS) is a rare genetic disorder caused by the loss of paternal genes on chromosome 15. The Aberrant Behavior Checklist (ABC) is a standardized rating scale for assessing problematic behaviors in persons with developmental disabilities. Our study aims to describe ABC scores in youth with PWS and track their change over time. The analysis included 69 patients. Mean ABC scores were compared in four age groups (5-8, 9-12, 13-16, and 17-22 years). A statistically significant difference was found only in the Irritability subscale, with lower scores in the 5-8 age group compared to the 9-12 age group. For change over time, scores for Irritability, Lethargy, Stereotypic Behavior, Hyperactivity subscales, and Total score were likely to decrease after age 12. Irritability subscale scores of males were predicted to increase more than those of females between ages of 5 and 12 . The Lethargy score in the nondeletion group had a greater reduction than the deletion group in the 12-20 year range. This study highlights the need for systematic collection and characterization of behavioral data given the burden of maladaptive behaviors that often persist for a lifetime.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Olga Bürger, Angelika Humbel, Ivan Ivanovski, Alessandra Baumer, Anita Rauch
Alterations in the X-linked recessive DMD gene cause dystrophinopathies with a broad clinical spectrum most commonly ranging from Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) to cardiomyopathy or intellectual disability. Carrier females are commonly unaffected but may show signs of dystrophinopathies. In addition, few asymptomatic male carriers with elevated creatine kinase levels have been described possibly related to deletions around exon 48. We now further support this assumed genotype-phenotype correlation by reporting an attenuated phenotype in a three-generation family with a deletion of exon 48 of the DMD gene with clinically unaffected carrier males and females. We confirmed deep intronic breakpoints in this family by genome sequencing, but such data are not available for published cases. Therefore, further observations are needed to clarify genotype-phenotype correlation in this region, since few reports also describe predicted in-frame copy number changes affecting this region in association with classical signs of dystrophinopathies.
X 连锁隐性 DMD 基因的改变会导致肌营养不良症,其临床表现范围很广,通常包括杜兴氏肌营养不良症(DMD)或贝克氏肌营养不良症(BMD)、心肌病或智力障碍。携带者女性通常不受影响,但可能表现出肌营养不良症的症状。此外,少数无症状的男性携带者肌酸激酶水平升高,这可能与外显子 48 附近的缺失有关。现在,我们进一步证实了这种假设的基因型与表型之间的相关性,我们报告了一个三代同堂的家族中,DMD 基因第 48 号外显子缺失的表型有所减弱,而临床上未受影响的男性和女性携带者均未受影响。我们通过基因组测序确认了该家族中的深内含子断点,但已发表的病例中没有此类数据。因此,还需要进一步观察,以明确该区域基因型与表型的相关性,因为很少有报道称该区域的框架内拷贝数变化与肌营养不良症的典型症状有关。
{"title":"Further evidence for an attenuated phenotype of in-frame DMD deletions affecting the central rod domain of dystrophin around exon 48.","authors":"Olga Bürger, Angelika Humbel, Ivan Ivanovski, Alessandra Baumer, Anita Rauch","doi":"10.1002/ajmg.a.63842","DOIUrl":"https://doi.org/10.1002/ajmg.a.63842","url":null,"abstract":"<p><p>Alterations in the X-linked recessive DMD gene cause dystrophinopathies with a broad clinical spectrum most commonly ranging from Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) to cardiomyopathy or intellectual disability. Carrier females are commonly unaffected but may show signs of dystrophinopathies. In addition, few asymptomatic male carriers with elevated creatine kinase levels have been described possibly related to deletions around exon 48. We now further support this assumed genotype-phenotype correlation by reporting an attenuated phenotype in a three-generation family with a deletion of exon 48 of the DMD gene with clinically unaffected carrier males and females. We confirmed deep intronic breakpoints in this family by genome sequencing, but such data are not available for published cases. Therefore, further observations are needed to clarify genotype-phenotype correlation in this region, since few reports also describe predicted in-frame copy number changes affecting this region in association with classical signs of dystrophinopathies.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alex F Nisbet, Aravind Viswanathan, Andrew M George, Pedro Arias, Steven D Klein, Julian Nevado, Alejandro Parra, Patricia Pascual, Dominic J Romeo, Jair Tenorio-Castaño, Jesse A Taylor, Elaine H Zackai, Pablo Lapunzina, Jennifer M Kalish
Simpson-Golabi-Behmel syndrome (SGBS) is a rare congenital overgrowth condition characterized by macrosomia, macroglossia, coarse facial features, and development delays. It is caused by pathogenic variants in the GPC3 gene on chromosome Xq26.2. Here, we performed a comprehensive literature review and phenotyping of known patients with molecularly confirmed SGBS and reviewed a novel cohort of 22 patients. Using these data, we characterized the tumor risk for Wilms tumor and hepatoblastoma to suggest appropriate screening for this patient population. In addition, we discuss the phenotypic overlap between SGBS and Beckwith-Wiedemann Spectrum.
{"title":"Phenotypic spectrum and tumor risk in Simpson-Golabi-Behmel syndrome: Case series and comprehensive literature review.","authors":"Alex F Nisbet, Aravind Viswanathan, Andrew M George, Pedro Arias, Steven D Klein, Julian Nevado, Alejandro Parra, Patricia Pascual, Dominic J Romeo, Jair Tenorio-Castaño, Jesse A Taylor, Elaine H Zackai, Pablo Lapunzina, Jennifer M Kalish","doi":"10.1002/ajmg.a.63840","DOIUrl":"https://doi.org/10.1002/ajmg.a.63840","url":null,"abstract":"<p><p>Simpson-Golabi-Behmel syndrome (SGBS) is a rare congenital overgrowth condition characterized by macrosomia, macroglossia, coarse facial features, and development delays. It is caused by pathogenic variants in the GPC3 gene on chromosome Xq26.2. Here, we performed a comprehensive literature review and phenotyping of known patients with molecularly confirmed SGBS and reviewed a novel cohort of 22 patients. Using these data, we characterized the tumor risk for Wilms tumor and hepatoblastoma to suggest appropriate screening for this patient population. In addition, we discuss the phenotypic overlap between SGBS and Beckwith-Wiedemann Spectrum.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ignacio Arroyo Carrera, Almudena Amor-Salamanca, Elena Márquez Isidro, Marlene Pérez-Barbeito, Ana Raquel Barrio Sacristán, Juan Pablo Ochoa
Marfan syndrome (MFS) is a hereditary systemic connective tissue disorder with great clinical variability. It is caused by heterozygous pathogenic variants in the FBN1 gene. Cardinal manifestations involve the cardiovascular, ocular, and skeletal systems. Clinical diagnosis is based on the revised Ghent nosology. We present the case of a child with a Marfan systemic score of 9 whose genetic study revealed two pathogenic mosaic frameshift variants in the FBN1 gene. Mosaicism is very rare in patients diagnosed with MFS, and this is the first description of a patient with two pathogenic mosaic variants in the FBN1 gene. Both variants are present in cells derived from ectodermal (buccal swab) and mesodermal (leukocyte) tissues, suggesting a mutation prior to gastrulation. We propose a defective repair of the de novo variant in the complementary strand as the mechanism that led this individual to be a carrier of two different populations of mutant cells carrying adjacent variants.
{"title":"Double somatic mosaicism in Marfan syndrome.","authors":"Ignacio Arroyo Carrera, Almudena Amor-Salamanca, Elena Márquez Isidro, Marlene Pérez-Barbeito, Ana Raquel Barrio Sacristán, Juan Pablo Ochoa","doi":"10.1002/ajmg.a.63831","DOIUrl":"https://doi.org/10.1002/ajmg.a.63831","url":null,"abstract":"<p><p>Marfan syndrome (MFS) is a hereditary systemic connective tissue disorder with great clinical variability. It is caused by heterozygous pathogenic variants in the FBN1 gene. Cardinal manifestations involve the cardiovascular, ocular, and skeletal systems. Clinical diagnosis is based on the revised Ghent nosology. We present the case of a child with a Marfan systemic score of 9 whose genetic study revealed two pathogenic mosaic frameshift variants in the FBN1 gene. Mosaicism is very rare in patients diagnosed with MFS, and this is the first description of a patient with two pathogenic mosaic variants in the FBN1 gene. Both variants are present in cells derived from ectodermal (buccal swab) and mesodermal (leukocyte) tissues, suggesting a mutation prior to gastrulation. We propose a defective repair of the de novo variant in the complementary strand as the mechanism that led this individual to be a carrier of two different populations of mutant cells carrying adjacent variants.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amaro Freire de Queiroz Júnior, Maria Teresa Vieira Sanseverino, Marcus Vinicius Martins Collares, Adriana Fornari, Luiza Amaral do Virmond, João Oliveira Bosco Filho, Osvaldo Artigalás, Têmis Maria Félix
Holoprosencephaly (HPE) results from a lack of cleavage of the prosencephalon. It has a complex etiology, resulting from chromosome abnormalities or single gene variants in the Sonic hedgehog signaling pathway. A single variant, p.Arg535Cys in CNOT1, has been described in HPE in association with pancreatic agenesis and neonatal diabetes. Here, we report on a case of HPE and p.Arg535Cys in CNOT1 without pancreatic agenesis where the patient presented with diabetes mellitus in adolescence. This case reinforces the role of CNOT1 in pancreatic development. We suggest that individuals with p.Arg535Cys in CNOT1 with no pancreas abnormalities observed at birth should be screened for diabetes during follow-up.
{"title":"CNOT1 p.Arg535Cys variant in holoprosencephaly with late onset diabetes mellitus.","authors":"Amaro Freire de Queiroz Júnior, Maria Teresa Vieira Sanseverino, Marcus Vinicius Martins Collares, Adriana Fornari, Luiza Amaral do Virmond, João Oliveira Bosco Filho, Osvaldo Artigalás, Têmis Maria Félix","doi":"10.1002/ajmg.a.63836","DOIUrl":"https://doi.org/10.1002/ajmg.a.63836","url":null,"abstract":"<p><p>Holoprosencephaly (HPE) results from a lack of cleavage of the prosencephalon. It has a complex etiology, resulting from chromosome abnormalities or single gene variants in the Sonic hedgehog signaling pathway. A single variant, p.Arg535Cys in CNOT1, has been described in HPE in association with pancreatic agenesis and neonatal diabetes. Here, we report on a case of HPE and p.Arg535Cys in CNOT1 without pancreatic agenesis where the patient presented with diabetes mellitus in adolescence. This case reinforces the role of CNOT1 in pancreatic development. We suggest that individuals with p.Arg535Cys in CNOT1 with no pancreas abnormalities observed at birth should be screened for diabetes during follow-up.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abdullah Sezer, Zeynep Özdemir, Erdem Özkan, Semra Çetinkaya
Aplasia Cutis Congenita with Ectrodactyly Skeletal Syndrome (ACCES, OMIM #619959) is an extremely rare multiple congenital anomalies syndrome caused by haploinsufficiency of the UBA2 gene. This syndrome presents with growth retardation, dysmorphic facial features, neurodevelopmental delay, skeletal problems including ectrodactyly, developmental dysplasia of the hip (DDH) and scoliosis, skin findings such as aplasia cutis, and some internal organ abnormalities. Our 13-year-old female patient and her 38-year-old father had a skeletal dysplasia phenotype with disproportionate short stature, bilateral DDH, mild epiphyseal involvement, scoliosis, and increased lumbar lordosis. Both were neurodevelopmentally normal and had mild dysmorphic facial features and mild ectodermal findings. The dominant inheritance pattern in the pedigree suggested a pre-diagnosis of spondyloepiphyseal dysplasia tarda. The exome sequencing analysis of the patient has identified a novel heterozygous variant, NM_005499.2:c.460-2A >G, in the UBA2 gene, and the father was found heterozygous either. The isolated spondyloepiphyseal involvement of our patients was an unusual presentation compared to patients with ACCES syndrome previously reported in the literature. Considering the highly variable expressiveness of ACCES syndrome and the co-occurrence of familial hip dysplasia and vertebral problems, we suggest that this syndrome can also be classified under "Spondyloepi(meta)physial dysplasia (SE(M)D)" in the nosology of genetic skeletal disorders.
{"title":"Atypical presentation of ACCES syndrome resembling dominant Spondyloepiphyseal dysplasia tarda.","authors":"Abdullah Sezer, Zeynep Özdemir, Erdem Özkan, Semra Çetinkaya","doi":"10.1002/ajmg.a.63852","DOIUrl":"https://doi.org/10.1002/ajmg.a.63852","url":null,"abstract":"<p><p>Aplasia Cutis Congenita with Ectrodactyly Skeletal Syndrome (ACCES, OMIM #619959) is an extremely rare multiple congenital anomalies syndrome caused by haploinsufficiency of the UBA2 gene. This syndrome presents with growth retardation, dysmorphic facial features, neurodevelopmental delay, skeletal problems including ectrodactyly, developmental dysplasia of the hip (DDH) and scoliosis, skin findings such as aplasia cutis, and some internal organ abnormalities. Our 13-year-old female patient and her 38-year-old father had a skeletal dysplasia phenotype with disproportionate short stature, bilateral DDH, mild epiphyseal involvement, scoliosis, and increased lumbar lordosis. Both were neurodevelopmentally normal and had mild dysmorphic facial features and mild ectodermal findings. The dominant inheritance pattern in the pedigree suggested a pre-diagnosis of spondyloepiphyseal dysplasia tarda. The exome sequencing analysis of the patient has identified a novel heterozygous variant, NM_005499.2:c.460-2A >G, in the UBA2 gene, and the father was found heterozygous either. The isolated spondyloepiphyseal involvement of our patients was an unusual presentation compared to patients with ACCES syndrome previously reported in the literature. Considering the highly variable expressiveness of ACCES syndrome and the co-occurrence of familial hip dysplasia and vertebral problems, we suggest that this syndrome can also be classified under \"Spondyloepi(meta)physial dysplasia (SE(M)D)\" in the nosology of genetic skeletal disorders.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hannah Lahey, Haewon Shin, Katherine Myers, Kim L McBride
Vascular Ehlers-Danlos, Marfan and Loeys-Dietz syndromes have increased risk of aortic dilation and dissection. Previous early studies showed hypermobile Ehlers-Danlos syndrome (hEDS) may also have increased risk, with echocardiography screening recommended; subsequent studies have not confirmed the risk or recommended echocardiography. This pediatric-based study assessed aortic dilation prevalence in those with hEDS by serial echocardiographic examinations and assessed family history for aortic dissections. We retrospectively identified individuals with hEDS who had echocardiography studies from the electronic medical records at one pediatric center. Aortic root Z-scores >2.0 were found in 15/225 subjects (average age 12.9 years) on initial echocardiograms, with no Z-score >3.0. Subsequent studies (n = 68) found statistically significant decline in aortic root Z-scores. Repeat echocardiography in those with initial aortic root Z-score >2.0 (n = 10) demonstrated a decline in Z score <2.0 in seven. On final examination, 9/225 (4.0%) had a Z-score >2.0, not statistically different from the general population. No aortic dissection occurred in first- or second-degree relatives. In conclusion, aortic root dilation rate in hEDS is likely not different from the general population. We propose that in the absence of other cardiac findings or suspicion for another disorder, echocardiography is not required in hEDS.
血管性埃勒斯-丹洛斯综合征、马凡综合征和洛伊-迪茨综合征会增加主动脉扩张和夹层的风险。之前的早期研究显示,活动度过高的埃勒斯-丹洛斯综合征(hEDS)也可能会增加风险,建议进行超声心动图筛查;随后的研究并未证实这一风险,也未建议进行超声心动图检查。这项以儿科为基础的研究通过连续超声心动图检查评估了 hEDS 患者主动脉扩张的患病率,并评估了主动脉夹层的家族史。我们从一家儿科中心的电子病历中回顾性地识别了接受过超声心动图检查的 hEDS 患者。在最初的超声心动图检查中,15/225 名受试者(平均年龄 12.9 岁)的主动脉根部 Z 值大于 2.0,没有 Z 值大于 3.0 的受试者。随后的研究(n = 68)发现主动脉根部 Z 评分在统计学上有显著下降。对初始主动脉根部 Z 评分大于 2.0 的患者(10 人)进行的重复超声心动图检查显示,Z 评分下降了 2.0,与普通人群无统计学差异。一级或二级亲属中均未发生主动脉夹层。总之,hEDS 患者的主动脉根部扩张率可能与普通人群无异。我们建议,在没有其他心脏检查结果或怀疑有其他疾病的情况下,hEDS 不需要进行超声心动图检查。
{"title":"Longitudinal echocardiography in pediatric patients with hypermobile Ehlers-Danlos syndrome.","authors":"Hannah Lahey, Haewon Shin, Katherine Myers, Kim L McBride","doi":"10.1002/ajmg.a.63844","DOIUrl":"https://doi.org/10.1002/ajmg.a.63844","url":null,"abstract":"<p><p>Vascular Ehlers-Danlos, Marfan and Loeys-Dietz syndromes have increased risk of aortic dilation and dissection. Previous early studies showed hypermobile Ehlers-Danlos syndrome (hEDS) may also have increased risk, with echocardiography screening recommended; subsequent studies have not confirmed the risk or recommended echocardiography. This pediatric-based study assessed aortic dilation prevalence in those with hEDS by serial echocardiographic examinations and assessed family history for aortic dissections. We retrospectively identified individuals with hEDS who had echocardiography studies from the electronic medical records at one pediatric center. Aortic root Z-scores >2.0 were found in 15/225 subjects (average age 12.9 years) on initial echocardiograms, with no Z-score >3.0. Subsequent studies (n = 68) found statistically significant decline in aortic root Z-scores. Repeat echocardiography in those with initial aortic root Z-score >2.0 (n = 10) demonstrated a decline in Z score <2.0 in seven. On final examination, 9/225 (4.0%) had a Z-score >2.0, not statistically different from the general population. No aortic dissection occurred in first- or second-degree relatives. In conclusion, aortic root dilation rate in hEDS is likely not different from the general population. We propose that in the absence of other cardiac findings or suspicion for another disorder, echocardiography is not required in hEDS.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Idit Maya, Michal Levy, Reut Matar, Sarit Kahana, Ifaat Agmon-Fishman, Cochava Klein, Merav Gurevitch, Lina Basel-Salmon, Lena Sagi-Dain
Long contiguous stretches of homozygosity or regions of homozygosity (ROH) are frequently detected via microarray and sequencing technologies. However, consensus on the establishment of specific size cutoffs for reporting ROH remains elusive. This study aims to assess the Total ROH Percentages (TRPS) and size of ROH segments across different ethnic origins, exploring potential disparities and proposing tailored diagnostic thresholds. This retrospective study included 13,035 microarray analyses conducted between 2017 to 2023. ROH segments on autosomal chromosomes were retrieved, and samples lacking ROH segments were excluded. The cohort was categorized based on reported ethnic origins, and TRPS and ROH segment size were analyzed for each origin. Distinct TRPS values were noted among different ethnic groups, ranging from median 0.36% in Ethiopian Jewish cohort and up to 6.42% in the Bedouin population. Wide range of 99th percentiles of ROH segment size for various origins was noted, ranging from 10.6 to 51.5 Mb. A significant correlation between ROH segment sizes and TRPS was noted in each origin. Statistically significant differences in ROH segment sizes were noted between the Jewish and the Israeli Arab/Druze origins in TRPS from 1% to 9.99%, whereas extremities of low (0.11%-0.99%) and high (over 10%) TRPS yielded no significant differences. In conclusion, as fixed absolute size thresholds may overlook pathogenic segments in certain populations while generating excessive reports in others, tailored approaches to define ROH reporting thresholds can be considered to facilitate the accuracy and clinical relevance of genomic analyses.
{"title":"Regions of Homozygocity size patterns among diverse ethnic groups in Israel: Toward tailored diagnostic reporting thresholds.","authors":"Idit Maya, Michal Levy, Reut Matar, Sarit Kahana, Ifaat Agmon-Fishman, Cochava Klein, Merav Gurevitch, Lina Basel-Salmon, Lena Sagi-Dain","doi":"10.1002/ajmg.a.63839","DOIUrl":"https://doi.org/10.1002/ajmg.a.63839","url":null,"abstract":"<p><p>Long contiguous stretches of homozygosity or regions of homozygosity (ROH) are frequently detected via microarray and sequencing technologies. However, consensus on the establishment of specific size cutoffs for reporting ROH remains elusive. This study aims to assess the Total ROH Percentages (TRPS) and size of ROH segments across different ethnic origins, exploring potential disparities and proposing tailored diagnostic thresholds. This retrospective study included 13,035 microarray analyses conducted between 2017 to 2023. ROH segments on autosomal chromosomes were retrieved, and samples lacking ROH segments were excluded. The cohort was categorized based on reported ethnic origins, and TRPS and ROH segment size were analyzed for each origin. Distinct TRPS values were noted among different ethnic groups, ranging from median 0.36% in Ethiopian Jewish cohort and up to 6.42% in the Bedouin population. Wide range of 99th percentiles of ROH segment size for various origins was noted, ranging from 10.6 to 51.5 Mb. A significant correlation between ROH segment sizes and TRPS was noted in each origin. Statistically significant differences in ROH segment sizes were noted between the Jewish and the Israeli Arab/Druze origins in TRPS from 1% to 9.99%, whereas extremities of low (0.11%-0.99%) and high (over 10%) TRPS yielded no significant differences. In conclusion, as fixed absolute size thresholds may overlook pathogenic segments in certain populations while generating excessive reports in others, tailored approaches to define ROH reporting thresholds can be considered to facilitate the accuracy and clinical relevance of genomic analyses.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}