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1. A novel variant in the COL6A1 gene causing Ullrich congenital muscular dystrophy in a consanguineous family: a case report

Author

Nirmala Dushyanthi Sirisena, U. M. Jayami Eshana Samaranayake, Osorio Lopes Abath Neto, A. Reghan Foley, B. A. P. Sajeewani Pathirana, Nilaksha Neththikumara, C. Sampath Paththinige, Pyara Rathnayake, Sandra Donkervoort, Carsten G. Bönnemann, and Vajira H. W. Dissanayake

Subjects
Case report, COL6A1, Collagen type VI, Consanguineous, Myopathy, Phenotypic heterogeneity, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Collagen VI-related dystrophies are a subtype of congenital muscular dystrophy caused by pathogenic variants in COL6A1, COL6A2 or COL6A3 genes affecting skeletal muscles and connective tissue. The clinical phenotype ranges from the milder Bethlem myopathy to the severe Ullrich congenital muscular dystrophy (UCMD). Herein, we report the first consanguineous Sri Lankan family with two children affected with UCMD due to a novel variant in the COL6A1 gene. Case presentation Two sisters, aged 10-years and 7-years, presented with progressive, bilateral proximal muscle weakness. Both probands had delayed motor milestones and demonstrated difficulty in standing from a squatting position, climbing stairs and raising arms above the shoulders. Cognitive, language and social development were age appropriate. Examination showed proximal muscle weakness of the upper and lower extremities and hyperlaxity of the wrist and fingers in both with some variability in clinical severity noted between the two siblings. Serum creatine kinase levels were elevated, and electromyography showed low polyphasic motor unit potentials in the 10-year-old and myopathic features with short duration motor unit potentials with no polyphasia in the 7-year-old. Whole exome sequencing (WES) was performed and a novel, homozygous missense, likely pathogenic variant in exon 25 of COL6A1 gene [NM_001848: c.1667G > T;NP_001839.2:p.Gly556Val] was identified in both probands. This variant was validated by Sanger sequencing in proband 1 as well as proband 2, and the parents and an unaffected sibling were found to be heterozygote carriers for the same variant. Conclusions The findings in this family add to the expanding number of COL6A1 variants identified and provides a better understanding of the genotype-phenotype correlations associated with UCMD.

Published
2021
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2. A novel variant in the COL6A1 gene causing Ullrich congenital muscular dystrophy in a consanguineous family: a case report

Author

Pyara Rathnayake, A. Reghan Foley, C. Sampath Paththinige, Nirmala D. Sirisena, Vajira H. W. Dissanayake, B. A. P. Sajeewani Pathirana, Sandra Donkervoort, Carsten G. Bönnemann, U. M. Jayami Eshana Samaranayake, Osorio Abath Neto, and Nilaksha Neththikumara

Subjects
Proband, Pathology, medicine.medical_specialty, Proximal muscle weakness, Ullrich congenital muscular dystrophy, Myopathy, COL6A1, Muscular Dystrophies, lcsh:RC346-429, Consanguinity, 03 medical and health sciences, 0302 clinical medicine, Consanguineous, Case report, medicine, Humans, Missense mutation, Child, Phenotypic heterogeneity, lcsh:Neurology. Diseases of the nervous system, Exome sequencing, Sri Lanka, 030304 developmental biology, 0303 health sciences, Sclerosis, Collagen type VI, business.industry, Bethlem myopathy, General Medicine, medicine.disease, Congenital muscular dystrophy, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Background Collagen VI-related dystrophies are a subtype of congenital muscular dystrophy caused by pathogenic variants in COL6A1, COL6A2 or COL6A3 genes affecting skeletal muscles and connective tissue. The clinical phenotype ranges from the milder Bethlem myopathy to the severe Ullrich congenital muscular dystrophy (UCMD). Herein, we report the first consanguineous Sri Lankan family with two children affected with UCMD due to a novel variant in the COL6A1 gene. Case presentation Two sisters, aged 10-years and 7-years, presented with progressive, bilateral proximal muscle weakness. Both probands had delayed motor milestones and demonstrated difficulty in standing from a squatting position, climbing stairs and raising arms above the shoulders. Cognitive, language and social development were age appropriate. Examination showed proximal muscle weakness of the upper and lower extremities and hyperlaxity of the wrist and fingers in both with some variability in clinical severity noted between the two siblings. Serum creatine kinase levels were elevated, and electromyography showed low polyphasic motor unit potentials in the 10-year-old and myopathic features with short duration motor unit potentials with no polyphasia in the 7-year-old. Whole exome sequencing (WES) was performed and a novel, homozygous missense, likely pathogenic variant in exon 25 of COL6A1 gene [NM_001848: c.1667G > T;NP_001839.2:p.Gly556Val] was identified in both probands. This variant was validated by Sanger sequencing in proband 1 as well as proband 2, and the parents and an unaffected sibling were found to be heterozygote carriers for the same variant. Conclusions The findings in this family add to the expanding number of COL6A1 variants identified and provides a better understanding of the genotype-phenotype correlations associated with UCMD.

Published
2021

3. Turner syndrome in diverse populations

Author

Joanna Y.L. Tung, Katta M. Girisha, Paul Kruszka, Nicole Fleischer, Engy A. Ashaat, E.V. Badoe, Dalia Farouk Hussen, Neer Shoba Chitrakar, Angélica Moresco, Neveen A. Ashaat, Olufemi Fasanmade, Siddaramappa J. Patil, Mona O. El Ruby, André Mégarbané, Johnathan Watts, Karen Fieggen, Gary T. K. Mok, Dhanya Yesodharan, Milagros M. Dueñas-Roque, Ezana Lulseged, Cedrik Tekendo-Ngongang, Sarah Savage, Saumya Shekhar Jamuar, Vajira H. W. Dissanayake, Nirmala D. Sirisena, Sultana M.H. Faradz, Antonio Richieri-Costa, Kelly L. Jones, Jasmine Chew Yin Goh, Brenda C. Iriele, María Beatriz de Herreros, Brian H.Y. Chung, Godfrey Mutashambara Rwegerera, María Gabriela Obregon, Yonit A. Addissie, Nydia Rena Benita Sihombing, Teresa Aravena, Shubha R. Phadke, Victoria Huckstadt, C. Sampath Paththinige, Meow-Keong Thong, Neerja Gupta, Agustini Utari, Sheela Nampoothiri, Elizabeth Eberechi Oyenusi, Ekanem N. Ekure, Maximilian Muenke, Rupesh Mishra, Oluwarotimi Bolaji Olopade, Annette Uwineza, Vorasuk Shotelersuk, and Ambroise Wonkam

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, Population, Cubitus valgus, Turner Syndrome, Physical examination, Short stature, Article, White People, Young Adult, Asian People, Turner syndrome, Genetics, medicine, Humans, Abnormalities, Multiple, SÍNDROME DE NOONAN, Child, education, Genetics (clinical), X chromosome, Chromosomes, Human, X, education.field_of_study, medicine.diagnostic_test, business.industry, Noonan Syndrome, Infant, Newborn, Area under the curve, Infant, Hispanic or Latino, Middle Aged, medicine.disease, Phenotype, Child, Preschool, Face, Population Surveillance, Noonan syndrome, Female, medicine.symptom, business, Facial Recognition
Abstract

Turner syndrome (TS) is a common multiple congenital anomaly syndrome resulting from complete or partial absence of the second X chromosome. TS presents with short stature, infertility secondary to ovarian dysgenesis, cardiac and renal anomalies, characteristic exam findings such as cubitus valgus, normal intelligence, and specific neurocognitive profile which includes visual spacial deficits and math difficulties. Clinical studies of TS have predominantly focused on individuals of European descent. In this study, we explore the phenotype of TS in diverse populations using clinical examination and facial analysis technology. Clinical data from 70 individuals and images from 108 individuals with TS from 18 different countries were analyzed. Individuals were grouped into categories of African descent (African), Asian, Latin American, Caucasian (European descent), and Middle Eastern. The most common phenotype features across all population groups were short stature (85%), cubitus valgus (77%) and, low posterior hair line 70%. Other phenotype features found in over half included small mandible (63%), narrow hyperconvex and deep set fingernails (56%), narrow maxilla (53%), and short fourth metacarpals (50%). Congenital heart disease was found in 32% of the cohort. Two facial analysis technology experiments were conducted: TS vs. general population and TS vs. Noonan syndrome. Across all ethnicities, facial analysis was very accurate in diagnosing TS from frontal facial images as measured by the area under the curve (AUC). An AUC of 0.903 (p

Published
2020

4. Williams–Beuren syndrome in diverse populations

Author

Antonio R. Porras, Meow-Keong Thong, Katta M. Girisha, Miguel Chávez Pastor, Angélica Moresco, Premala Muthukumarasamy, María Gabriela Obregon, Ee Shien Tan, Gary T. K. Mok, Maximilian Muenke, Engela Honey, Cedrik Tekendo-Ngongang, Alec P. Boyle, E.V. Badoe, Laila Bouguenouch, Colleen A. Morris, Rupesh Mishra, Angeline Lai, Bertha Elena Gallardo Jugo, Adebowale Adeyemo, Deise Helena de Souza, Saumya Shekhar Jamuar, María Beatriz de Herreros, Karim Ouldim, Beth A. Kozel, Ashleigh D. Gill, Danilo Moretti-Ferreira, Mieke M. van Haelst, Ivan F M Lo, Vajira H. W. Dissanayake, Pranoot Tanpaiboon, Carlos Ferreira, Nirmala D. Sirisena, Leah Dowsett, Marshall L. Summar, Tommy Hu, Hugo Hernán Abarca Barriga, Dalia Farouk Hussen, Monisha S. Kisling, Milana Trubnykova, Ni-Chung Lee, Victoria Huckstadt, Marius George Linguraru, A. Micheil Innes, Eloise J. Prijoles, Vorasuk Shotelersuk, Khadija Belhassan, Brian H.Y. Chung, Jiin Ying Lim, Paul Kruszka, Anju Shukla, Ramses Badilla-Porras, Roger E. Stevenson, Siddaramappa J. Patil, Yonit A. Addissie, C. Sampath Paththinige, Ambroise Wonkam, Ihssane El Bouchikhi, Engy A. Ashaat, Mona O. El Ruby, Stephanie Lotz-Esquivel, André Mégarbané, Jorge La Serna, Cham Breana Wen-Min, HM Luk, Karen Fieggen, Alison Eaton, Neerja Gupta, Kelly L. Jones, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), and Human genetics

Subjects
Williams Syndrome, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Pediatrics, medicine.medical_specialty, Population, Ethnic group, 030105 genetics & heredity, Sensitivity and Specificity, Article, Genetic Heterogeneity, 03 medical and health sciences, Population Groups, Intellectual disability, Genetics, medicine, Humans, cardiovascular diseases, education, Genetics (clinical), education.field_of_study, Anthropometry, Genetic heterogeneity, business.industry, Facies, Reproducibility of Results, Microdeletion syndrome, medicine.disease, Phenotype, Biological Variation, Population, Cohort, Williams syndrome, business
Abstract

Williams-Beuren syndrome (WBS) is a common microdeletion syndrome characterized by a 1.5Mb deletion in 7q11.23. The phenotype of WBS has been well described in populations of European descent with not as much attention given to other ethnicities. In this study, individuals with WBS from diverse populations were assessed clinically and by facial analysis technology. Clinical data and images from 137 individuals with WBS were found in 19 countries with an average age of 11 years and female gender of 45%. The most common clinical phenotype elements were periorbital fullness and intellectual disability which were present in greater than 90% of our cohort. Additionally, 75% or greater of all individuals with WBS had malar flattening, long philtrum, wide mouth, and small jaw. Using facial analysis technology, we compared 286 Asian, African, Caucasian, and Latin American individuals with WBS with 286 gender and age matched controls and found that the accuracy to discriminate between WBS and controls was 0.90 when the entire cohort was evaluated concurrently. The test accuracy of the facial recognition technology increased significantly when the cohort was analyzed by specific ethnic population (P-value

Published
2018

5. 22q11.2 deletion syndrome in diverse populations

Author

Gary T. K. Mok, Nirmala D. Sirisena, Julie D. Kaplan, Christopher C.Y. Mak, Paul Kruszka, Nnenna Kalu, T. Blaine Crowley, Adebowale Adeyemo, Siddaramappa J. Patil, Vera Lúcia Gil-da-Silva-Lopes, C. Sampath Paththinige, Antonio Richieri-Costa, Daniel E. McGinn, Kelly L. Jones, Marius George Linguraru, Vorasuk Shotelersuk, Donna M. McDonald-McGinn, Jordann-Mishael Duncan, Ogochukwu J. Sokunbi, L. B. Lahiru Prabodha, Maximilian Muenke, Premala Muthukumarasamy, Vajira H. W. Dissanayake, Omar A. Abdul-Rahman, Brian H.Y. Chung, Annette Uwineza, Marshall L. Summar, Yonit A. Addissie, Elijah Biggs, Elaine H. Zackai, María Gabriela Obregon, Antonio R. Porras, Ekanem N. Ekure, Meow-Keong Thong, Angélica Moresco, Rupesh Mishra, Carlos Ferreira, Leon Mutesa, and Matthew Share

Subjects
0301 basic medicine, Genetics, education.field_of_study, Heart disease, African descent, Population, Ethnic group, Microdeletion syndrome, Biology, medicine.disease, 03 medical and health sciences, 030104 developmental biology, DiGeorge syndrome, Variable phenotype, medicine, Deletion syndrome, education, Genetics (clinical), Demography
Abstract

22q11.2 deletion syndrome (22q11.2 DS) is the most common microdeletion syndrome and is underdiagnosed in diverse populations. This syndrome has a variable phenotype and affects multiple systems, making early recognition imperative. In this study, individuals from diverse populations with 22q11.2 DS were evaluated clinically and by facial analysis technology. Clinical information from 106 individuals and images from 101 were collected from individuals with 22q11.2 DS from 11 countries; average age was 11.7 and 47% were male. Individuals were grouped into categories of African descent (African), Asian, and Latin American. We found that the phenotype of 22q11.2 DS varied across population groups. Only two findings, congenital heart disease and learning problems, were found in greater than 50% of participants. When comparing the clinical features of 22q11.2 DS in each population, the proportion of individuals within each clinical category was statistically different except for learning problems and ear anomalies (P

Published
2017

6. Down syndrome in diverse populations

Author

Marius George Linguraru, Vorasuk Shotelersuk, Brian H.Y. Chung, J. Joseph Brough, Angélica Moresco, Maximilian Muenke, Katherine L. Pardo, Christy A. N. Okoromah, Desmond Ikebudu, Omar A. Abdul-Rahman, Ogochukwu J. Sokunbi, Samantha La Qua, Gary T. K. Mok, María Gabriela Obregon, Yonit A. Addissie, Antonio R. Porras, Vajira H. W. Dissanayake, Breana Cham Wen Min, Meow-Keong Thong, Felicia Ikolo, Marshall L. Summar, Andrew K. Sobering, Ni-Chung Lee, Adebowale Adeyemo, Katta M. Girisha, Saumya Shekhar Jamuar, Leon Mutesa, Nnenna Kalu, C. Sampath Paththinige, Suma Ganesh, Antonio Richieri-Costa, Kelly L. Jones, Ivy Ng, Shailja Tibrewal, Nirmala D. Sirisena, Batriti Wallang, Premala Muthukumarasamy, Siddaramappa J. Patil, Annette Uwineza, Daniel Akinsanya Joseph, L. B. Lahiru Prabodha, Ekanem N. Ekure, Christopher Emeka Ugwu, and Paul Kruszka

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Down syndrome, Clinodactyly, Adolescent, SÍNDROME DE DOWN, Ethnic group, 030105 genetics & heredity, Sensitivity and Specificity, Young Adult, 03 medical and health sciences, Population Groups, Internal medicine, Genetics, medicine, Humans, Canthus, Child, Cognitive impairment, Genetic Association Studies, Genetics (clinical), Nose, business.industry, Infant, Newborn, Facies, Infant, medicine.disease, Phenotype, medicine.anatomical_structure, Case-Control Studies, Child, Preschool, Population Surveillance, Cohort, Female, Down Syndrome, medicine.symptom, business, Brachycephaly, Biomarkers
Abstract

Down syndrome is the most common cause of cognitive impairment and presents clinically with universally recognizable signs and symptoms. In this study, we focus on exam findings and digital facial analysis technology in individuals with Down syndrome in diverse populations. Photos and clinical information were collected on 65 individuals from 13 countries, 56.9% were male and the average age was 6.6 years (range 1 month to 26 years; SD = 6.6 years). Subjective findings showed that clinical features were different across ethnicities (Africans, Asians, and Latin Americans), including brachycephaly, ear anomalies, clinodactyly, sandal gap, and abundant neck skin, which were all significantly less frequent in Africans (P

Published
2016

10. Cover Image, Volume 176A, Number 5, May 2018

Author

Paul Kruszka, Antonio R. Porras, Deise Helena de Souza, Angélica Moresco, Victoria Huckstadt, Ashleigh D. Gill, Alec P. Boyle, Tommy Hu, Yonit A. Addissie, Gary T. K. Mok, Cedrik Tekendo‐Ngongang, Karen Fieggen, Eloise J. Prijoles, Pranoot Tanpaiboon, Engela Honey, Ho‐Ming Luk, Ivan F. M. Lo, Meow‐Keong Thong, Premala Muthukumarasamy, Kelly L. Jones, Khadija Belhassan, Karim Ouldim, Ihssane El Bouchikhi, Laila Bouguenouch, Anju Shukla, Katta M. Girisha, Nirmala D. Sirisena, Vajira H. W. Dissanayake, C. Sampath Paththinige, Rupesh Mishra, Monisha S. Kisling, Carlos R. Ferreira, María Beatriz de Herreros, Ni‐Chung Lee, Saumya S. Jamuar, Angeline Lai, Ee Shien Tan, Jiin Ying Lim, Cham Breana Wen‐Min, Neerja Gupta, Stephanie Lotz‐Esquivel, Ramsés Badilla‐Porras, Dalia Farouk Hussen, Mona O. El Ruby, Engy A. Ashaat, Siddaramappa J. Patil, Leah Dowsett, Alison Eaton, A. Micheil Innes, Vorasuk Shotelersuk, Ëben Badoe, Ambroise Wonkam, María Gabriela Obregon, Brian H. Y. Chung, Milana Trubnykova, Jorge La Serna, Bertha Elena Gallardo Jugo, Miguel Chávez Pastor, Hugo Hernán Abarca Barriga, Andre Megarbane, Beth A. Kozel, Mieke M. van Haelst, Roger E. Stevenson, Marshall Summar, A. Adebowale Adeyemo, Colleen A. Morris, Danilo Moretti‐Ferreira, Marius George Linguraru, and Maximilian Muenke

Subjects
Genetics, Genetics (clinical)
Published
2018

14. Cover Image, Volume 173A, Number 9, September 2017

Author

Paul Kruszka, Antonio R. Porras, Yonit A. Addissie, Angélica Moresco, Sofia Medrano, Gary T. K. Mok, Gordon K. C. Leung, Cedrik Tekendo-Ngongang, Annette Uwineza, Meow-Keong Thong, Premala Muthukumarasamy, Engela Honey, Ekanem N. Ekure, Ogochukwu J. Sokunbi, Nnenna Kalu, Kelly L. Jones, Julie D. Kaplan, Omar A. Abdul-Rahman, Lisa M. Vincent, Amber Love, Khadija Belhassan, Karim Ouldim, Ihssane El Bouchikhi, Anju Shukla, Katta M. Girisha, Siddaramappa J. Patil, Nirmala D. Sirisena, Vajira H. W. Dissanayake, C. Sampath Paththinige, Rupesh Mishra, Eva Klein-Zighelboim, Bertha E. Gallardo Jugo, Miguel Chávez Pastor, Hugo H. Abarca-Barriga, Steven A. Skinner, Eloise J. Prijoles, Eben Badoe, Ashleigh D. Gill, Vorasuk Shotelersuk, Patroula Smpokou, Monisha S. Kisling, Carlos R. Ferreira, Leon Mutesa, Andre Megarbane, Antonie D. Kline, Amy Kimball, Emmy Okello, Peter Lwabi, Twalib Aliku, Emmanuel Tenywa, Nonglak Boonchooduang, Pranoot Tanpaiboon, Antonio Richieri-Costa, Ambroise Wonkam, Brian H. Y. Chung, Roger E. Stevenson, Marshall Summar, Kausik Mandal, Shubha R. Phadke, María G. Obregon, Marius G. Linguraru, and Maximilian Muenke

Subjects
Genetics, Genetics (clinical)
Published
2017

15. Cover Image, Volume 173A, Number 4, April 2017

Author

Paul Kruszka, Yonit A. Addissie, Daniel E. McGinn, Antonio R. Porras, Elijah Biggs, Matthew Share, T. Blaine Crowley, Brian H. Y. Chung, Gary T. K. Mok, Christopher C. Y. Mak, Premala Muthukumarasamy, Meow-Keong Thong, Nirmala D. Sirisena, Vajira H. W. Dissanayake, C. Sampath Paththinige, L. B. Lahiru Prabodha, Rupesh Mishra, Vorasuk Shotelersuk, Ekanem Nsikak Ekure, Ogochukwu Jidechukwu Sokunbi, Nnenna Kalu, Carlos R. Ferreira, Jordann-Mishael Duncan, Siddaramappa Jagdish Patil, Kelly L. Jones, Julie D. Kaplan, Omar A. Abdul-Rahman, Annette Uwineza, Leon Mutesa, Angélica Moresco, María Gabriela Obregon, Antonio Richieri-Costa, Vera L. Gil-da-Silva-Lopes, Adebowale A. Adeyemo, Marshall Summar, Elaine H. Zackai, Donna M. McDonald-McGinn, Marius George Linguraru, and Maximilian Muenke

Subjects
Genetics, Genetics (clinical)
Published
2017

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