. 2024 May 3;384(6695):584-590.

doi: 10.1126/science.adl1624. Epub 2024 May 2.

Risk of meningomyelocele mediated by the common 22q11.2 deletion

Keng Ioi Vong^#^{1

2}, Sangmoon Lee^#^{1

2}, Kit Sing Au³, T Blaine Crowley⁴, Valeria Capra⁵, Jeremiah Martino⁶, Meade Haller⁷, Camila Araújo⁸, Hélio R Machado⁸, Renee George^{1

2}, Bryn Gerding^{1

2}, Kiely N James^{1

2}, Valentina Stanley^{1

2}, Nan Jiang^{1

2}, Kameron Alu^{1

2}, Naomi Meave^{1

2}, Anna S Nidhiry², Fiza Jiwani^{1

2}, Isaac Tang^{1

2}, Ashna Nisal^{1

2}, Ishani Jhamb^{1

2}, Arzoo Patel^{1

2}, Aakash Patel^{1

2}, Jennifer McEvoy-Venneri^{1

2}, Chelsea Barrows^{1

2}, Celina Shen^{1

2}, Yoo-Jin Ha^{1

2}, Robyn Howarth^{1

2}, Madison Strain⁹, Allison Elizabeth Ashley-Koch⁹, Matloob Azam¹⁰, Sara Mumtaz¹¹, Gyang Markus Bot¹², Richard H Finnell¹³, Zoha Kibar¹⁴, Ahmed I Marwan¹⁵, Gia Melikishvili¹⁶, Hal S Meltzer¹⁷, Osvaldo M Mutchinick¹⁸, David A Stevenson¹⁹, Henry J Mroczkowski²⁰, Betsy Ostrander²¹, Erica Schindewolf²², Julie Moldenhauer²², Elaine H Zackai⁴, Beverly S Emanuel⁴, Sixto Garcia-Minaur²³, Beata A Nowakowska²⁴, Roger E Stevenson²⁵, Maha S Zaki²⁶, Hope Northrup³, Hanna K McNamara²⁷, Kimberly A Aldinger^{27

28

29}, Ian G Phelps²⁸, Mei Deng²⁸, Ian A Glass²⁸; Spina Bifida Sequencing Consortium‡; Bernice Morrow³⁰, Donna M McDonald-McGinn^{4

31}, Simone Sanna-Cherchi⁶, Dolores J Lamb^{7

32}, Joseph G Gleeson^{1

2}

Collaborators, Affiliations

Collaborators

Spina Bifida Sequencing Consortium‡:
Allison Elizabeth Ashley Koch, Hal S Meltzer, Joan Le, Kit Sing Au, Hope Northrup, Gyang Markus Bot, Valeria Capra, Richard H Finnell, Zoha Kibar, Philip J Lupo, Helio R Machado, Camila Araújo, Tony Magana, Ahmed I Marwan, Gia Melikishvili, Osvaldo M Mutchinick, Roger E Stevenson, Anna Yurrita, Maha S Zaki, Sara Mumtaz, José Ramón Medina-Bereciartu, Caroline M Kolvenbach, Shirlee Shril, Friedhelm Hildebrandt, Mahmoud M Noureldeen, Aida Ms Salem, Yukitoshi Takahashi, Hormos Salimi-Dafsari, H Westley Phillips, Brian Hanak, Bülent Kara, Ayfer Sakarya Güneş, David D Gonda, Salman Kirmani, Tinatin Tkemaladze, Joseph G Gleeson

Affiliations

¹ Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
² Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
³ Department of Pediatrics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth) and Children's Memorial Hermann Hospital, Houston, TX 77030, USA.
⁴ 22q and You Center, Division of Human Genetics, Children's Hospital of Philadelphia and Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ Genomics and Clinical Genetics Unit, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy.
⁶ Division of Nephrology, Department of Medicine, Columbia University, NY 10027, USA.
⁷ Center for Reproductive Medicine, Department of Molecular and Cellular Biology and Scott Department of Urology, Baylor College of Medicine, TX 77030, USA.
⁸ Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14040-900, Brazil.
⁹ Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27710, USA.
¹⁰ Pediatrics and Child Neurology, Wah Medical College, Wah Cantt, Punjab 47000, Pakistan.
¹¹ Department of Biological Sciences, National University of Medical Sciences (NUMS), Punjab 46000, Pakistan.
¹² Neurosurgery Division, Department of Surgery, Jos University Teaching Hospital, Jos 930105, Nigeria.
¹³ Center for Precision Environmental Health, Departments of Molecular and Human Genetics, Molecular and Cellular Biology and Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁴ Department of Neurosciences, University of Montreal and CHU Sainte Justine Research Center, Montreal, QC H3T 1C5, Canada.
¹⁵ Division of Pediatric Surgery, University of Colorado School of Medicine, Children's Hospital of Colorado, Colorado Fetal Care Center, Aurora, CO 80045, USA.
¹⁶ Department of Pediatrics, MediClubGeorgia Medical Center, Tbilisi 0160, Georgia.
¹⁷ Department of Neurosurgery, University of California San Diego, Rady Children's Hospital, San Diego, CA 92123, USA.
¹⁸ Department of Genetics, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, 14080 Mexico City, Mexico.
¹⁹ Division of Medical Genetics, Stanford University, Palo Alto, CA 94305, USA.
²⁰ Division of Medical Genetics, University of Tennessee Health Science Campus, Memphis, TN 38163, USA.
²¹ Division of Pediatric Neurology, Primary Children's Hospital, University of Utah, Salt Lake City, UT 84113, USA.
²² Center for Fetal Diagnosis and Treatment, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
²³ Clinical Genetics Section, Institute of Medical and Molecular Genetics, University Hospital La Paz, 28046 Madrid, Spain.
²⁴ Department of Medical Genetics, Institute of Mother and Child, Kasprzaka, 01-211 Warsaw, Poland.
²⁵ JC Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA.
²⁶ Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
²⁷ Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
²⁸ Departments of Pediatrics, University of Washington, Seattle, WA 98105, USA.
²⁹ Department of Neurology, University of Washington, Seattle, WA 98105, USA.
³⁰ Division of Translational Genetics, Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
³¹ Department of Human Biology and Medical Genetics, Sapienza University, 00185-Rome RM, Italy.
³² Department of Urology, Center for Reproductive Genomics, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10021, USA.

^# Contributed equally.

PMID: 38696583
DOI: 10.1126/science.adl1624

Risk of meningomyelocele mediated by the common 22q11.2 deletion

Keng Ioi Vong et al. Science. 2024.

. 2024 May 3;384(6695):584-590.

doi: 10.1126/science.adl1624. Epub 2024 May 2.

Authors

Collaborators

Spina Bifida Sequencing Consortium‡:
Allison Elizabeth Ashley Koch, Hal S Meltzer, Joan Le, Kit Sing Au, Hope Northrup, Gyang Markus Bot, Valeria Capra, Richard H Finnell, Zoha Kibar, Philip J Lupo, Helio R Machado, Camila Araújo, Tony Magana, Ahmed I Marwan, Gia Melikishvili, Osvaldo M Mutchinick, Roger E Stevenson, Anna Yurrita, Maha S Zaki, Sara Mumtaz, José Ramón Medina-Bereciartu, Caroline M Kolvenbach, Shirlee Shril, Friedhelm Hildebrandt, Mahmoud M Noureldeen, Aida Ms Salem, Yukitoshi Takahashi, Hormos Salimi-Dafsari, H Westley Phillips, Brian Hanak, Bülent Kara, Ayfer Sakarya Güneş, David D Gonda, Salman Kirmani, Tinatin Tkemaladze, Joseph G Gleeson

Affiliations

¹ Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
² Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
³ Department of Pediatrics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth) and Children's Memorial Hermann Hospital, Houston, TX 77030, USA.
⁴ 22q and You Center, Division of Human Genetics, Children's Hospital of Philadelphia and Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ Genomics and Clinical Genetics Unit, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy.
⁶ Division of Nephrology, Department of Medicine, Columbia University, NY 10027, USA.
⁷ Center for Reproductive Medicine, Department of Molecular and Cellular Biology and Scott Department of Urology, Baylor College of Medicine, TX 77030, USA.
⁸ Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14040-900, Brazil.
⁹ Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27710, USA.
¹⁰ Pediatrics and Child Neurology, Wah Medical College, Wah Cantt, Punjab 47000, Pakistan.
¹¹ Department of Biological Sciences, National University of Medical Sciences (NUMS), Punjab 46000, Pakistan.
¹² Neurosurgery Division, Department of Surgery, Jos University Teaching Hospital, Jos 930105, Nigeria.
¹³ Center for Precision Environmental Health, Departments of Molecular and Human Genetics, Molecular and Cellular Biology and Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁴ Department of Neurosciences, University of Montreal and CHU Sainte Justine Research Center, Montreal, QC H3T 1C5, Canada.
¹⁵ Division of Pediatric Surgery, University of Colorado School of Medicine, Children's Hospital of Colorado, Colorado Fetal Care Center, Aurora, CO 80045, USA.
¹⁶ Department of Pediatrics, MediClubGeorgia Medical Center, Tbilisi 0160, Georgia.
¹⁷ Department of Neurosurgery, University of California San Diego, Rady Children's Hospital, San Diego, CA 92123, USA.
¹⁸ Department of Genetics, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, 14080 Mexico City, Mexico.
¹⁹ Division of Medical Genetics, Stanford University, Palo Alto, CA 94305, USA.
²⁰ Division of Medical Genetics, University of Tennessee Health Science Campus, Memphis, TN 38163, USA.
²¹ Division of Pediatric Neurology, Primary Children's Hospital, University of Utah, Salt Lake City, UT 84113, USA.
²² Center for Fetal Diagnosis and Treatment, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
²³ Clinical Genetics Section, Institute of Medical and Molecular Genetics, University Hospital La Paz, 28046 Madrid, Spain.
²⁴ Department of Medical Genetics, Institute of Mother and Child, Kasprzaka, 01-211 Warsaw, Poland.
²⁵ JC Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA.
²⁶ Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
²⁷ Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
²⁸ Departments of Pediatrics, University of Washington, Seattle, WA 98105, USA.
²⁹ Department of Neurology, University of Washington, Seattle, WA 98105, USA.
³⁰ Division of Translational Genetics, Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
³¹ Department of Human Biology and Medical Genetics, Sapienza University, 00185-Rome RM, Italy.
³² Department of Urology, Center for Reproductive Genomics, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10021, USA.

^# Contributed equally.

PMID: 38696583
DOI: 10.1126/science.adl1624

Abstract

Meningomyelocele is one of the most severe forms of neural tube defects (NTDs) and the most frequent structural birth defect of the central nervous system. We assembled the Spina Bifida Sequencing Consortium to identify causes. Exome and genome sequencing of 715 parent-offspring trios identified six patients with chromosomal 22q11.2 deletions, suggesting a 23-fold increased risk compared with the general population. Furthermore, analysis of a separate 22q11.2 deletion cohort suggested a 12- to 15-fold increased NTD risk of meningomyelocele. The loss of Crkl, one of several neural tube-expressed genes within the minimal deletion interval, was sufficient to replicate NTDs in mice, where both penetrance and expressivity were exacerbated by maternal folate deficiency. Thus, the common 22q11.2 deletion confers substantial meningomyelocele risk, which is partially alleviated by folate supplementation.

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Risk of meningomyelocele mediated by the common 22q11.2 deletion

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Risk of meningomyelocele mediated by the common 22q11.2 deletion

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