. 2024 Sep;26(9):101166.

doi: 10.1016/j.gim.2024.101166. Epub 2024 May 17.

Loss of function of FAM177A1, a Golgi complex localized protein, causes a novel neurodevelopmental disorder

Jennefer N Kohler¹, Nicole R Legro², Dustin Baldridge³, Jimann Shin³, Angela Bowman³, Berrak Ugur⁴, Madelyn M Jackstadt⁵, Leah P Shriver⁵, Gary J Patti⁵, Bo Zhang³, Wenjia Feng³, Anthony R McAdow³, Pagé Goddard⁶, Rachel A Ungar⁶, Tanner Jensen⁶, Kevin S Smith⁷, Laure Fresard⁸, Raquel Alvarez⁹, Devon Bonner¹⁰, Chloe M Reuter¹⁰, Colleen McCormack¹¹, Elijah Kravets¹¹, Shruti Marwaha¹¹, James M Holt¹²; Undiagnosed Diseases Network; Elizabeth A Worthey¹³, Euan A Ashley⁹, Stephen B Montgomery¹⁴, Paul G Fisher¹⁵, John Postlethwait¹⁶, Pietro De Camilli¹⁷, Lila Solnica-Krezel³, Jonathan A Bernstein¹⁰, Matthew T Wheeler⁹

Collaborators, Affiliations

Collaborators

Undiagnosed Diseases Network:
Maria T Acosta, Margaret Adam, David R Adams, Raquel L Alvarez, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A Ashley, Carlos A Bacino, Guney Bademci, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H Beggs, Edward Behrens, Gill Bejerano, Hugo J Bellen, Jimmy Bennett, Beverly Berg-Rood, Jonathan A Bernstein, Gerard T Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C Briere, Elizabeth A Burke, Lindsay C Burrage, Manish J Butte, Peter Byers, William E Byrd, John Carey, Olveen Carrasquillo, Thomas Cassini, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Ivan Chinn, Gary D Clark, Terra R Coakley, Laurel A Cobban, Joy D Cogan, Matthew Coggins, F Sessions Cole, Heather A Colley, Heidi Cope, Brian Corner, Rosario Corona, William J Craigen, Andrew B Crouse, Michael Cunningham, Precilla D'Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G Dayal, Esteban C Dell'Angelica, Patricia Dickson, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L Doss, Emilie D Douine, Dawn Earl, David J Eckstein, Lisa T Emrick, Christine M Eng, Kimberly Ezell, Marni Falk, Elizabeth L Fieg, Paul G Fisher, Brent L Fogel, Irman Forghani, William A Gahl, Ian Glass, Bernadette Gochuico, Page C Goddard, Rena A Godfrey, Katie Golden-Grant, Alana Grajewski, Don Hadley, Sihoun Hahn, Meghan C Halley, Rizwan Hamid, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M Hisama, Ingrid A Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Sarah Hutchison, Wendy Introne, Rosario Isasi, Kosuke Izumi, Fariha Jamal, Gail P Jarvik, Jeffrey Jarvik, Suman Jayadev, Orpa Jean-Marie, Vaidehi Jobanputra, Lefkothea Karaviti, Shamika Ketkar, Dana Kiley, Gonench Kilich, Shilpa N Kobren, Isaac S Kohane, Jennefer N Kohler, Susan Korrick, Mary Kozuira, Deborah Krakow, Donna M Krasnewich, Elijah Kravets, Seema R Lalani, Byron Lam, Christina Lam, Brendan C Lanpher, Ian R Lanza, Kimberly LeBlanc, Brendan H Lee, Roy Levitt, Richard A Lewis, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K Loo, Joseph Loscalzo, Richard L Maas, Ellen F Macnamara, Calum A MacRae, Valerie V Maduro, AudreyStephannie Maghiro, Rachel Mahoney, May Christine V Malicdan, Laura A Mamounas, Teri A Manolio, Rong Mao, Kenneth Maravilla, Ronit Marom, Gabor Marth, Beth A Martin, Martin G Martin, Julian A Martínez-Agosto, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Alexa T McCray, Elisabeth McGee, Heather Mefford, J Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo Moretti, John Mulvihill, Mariko Nakano-Okuno, Stanley F Nelson, Serena Neumann, John H Newman, Sarah K Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P Orengo, Laura Pace, Stephen Pak, J Carl Pallais, Christina G S Palmer, Jeanette C Papp, Neil H Parker, John A Phillips 3rd, Jennifer E Posey, Lorraine Potocki, Barbara N Pusey Swerdzewski, Aaron Quinlan, Deepak A Rao, Anna Raper, Wendy Raskind, Genecee Renteria, Chloe M Reuter, Lynette Rives, Amy K Robertson, Lance H Rodan, Jill A Rosenfeld, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B Sampson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A Scott, C Ron Scott, Elaine Seto, Vandana Shashi, Jimann Shin, Edwin K Silverman, Janet S Sinsheimer, Kathy Sisco, Edward C Smith, Kevin S Smith, Lilianna Solnica-Krezel, Ben Solomon, Rebecca C Spillmann, Joan M Stoler, Kathleen Sullivan, Jennifer A Sullivan, Angela Sun, Shirley Sutton, David A Sweetser, Virginia Sybert, Holly K Tabor, Queenie K-G Tan, Amelia L M Tan, Arjun Tarakad, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J Tifft, Camilo Toro, Alyssa A Tran, Rachel A Ungar, Tiina K Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P Vogel, Colleen E Wahl, Melissa Walker, Stephanie Wallace, Nicole M Walley, Jennifer Wambach, Jijun Wan, Michael F Wangler, Patricia A Ward, Daniel Wegner, Monika Weisz Hubshman, Mark Wener, Tara Wenger, Monte Westerfield, Matthew T Wheeler, Jordan Whitlock, Lynne A Wolfe, Kim Worley, Changrui Xiao, Shinya Yamamoto, John Yang, Zhe Zhang, Stephan Zuchner

Affiliations

¹ Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA; Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, Stanford, CA. Electronic address: jkohler@stanfordhealthcare.org.
² Department of Obstetrics and Gynecology, MedStar Washington Hospital Center and Georgetown University Hospital, Washington, DC. Electronic address: nicole.legro@gunet.georgetown.edu.
³ Model Organism Screening Center, Department of Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, MO.
⁴ Departments of Neuroscience and of Cell Biology, Yale University School of Medicine, New Haven, CT.
⁵ Department of Chemistry, Washington University in St. Louis, St. Louis, MO; Department of Medicine, Washington University in St. Louis, St. Louis, MO; Center for Proteomics, Metabolomics, and Isotope Tracing, Washington University in St. Louis, St. Louis, MO.
⁶ Department of Genetics, Stanford University School of Medicine, Stanford, CA.
⁷ Department of Pathology, Stanford University School of Medicine, Stanford, CA.
⁸ Invitae, San Francisco, CA.
⁹ Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA.
¹⁰ Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA; Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, Stanford, CA.
¹¹ Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA.
¹² PacBio, 1305 O'Brien Drive Menlo Park, CA.
¹³ Center for Computational Genomics and Data Science, Department of Genetics, University of Alabama, Birmingham, AL.
¹⁴ Department of Genetics, Stanford University School of Medicine, Stanford, CA; Department of Pathology, Stanford University School of Medicine, Stanford, CA.
¹⁵ Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA; Department of Pediatrics, Division of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA.
¹⁶ Institute of Neuroscience, University of Oregon, Eugene, OR.
¹⁷ Departments of Neuroscience and of Cell Biology, Howard Hughes Medical Institute, Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT.

PMID: 38767059
PMCID: PMC11451386 (available on 2025-09-01)
DOI: 10.1016/j.gim.2024.101166

Loss of function of FAM177A1, a Golgi complex localized protein, causes a novel neurodevelopmental disorder

Jennefer N Kohler et al. Genet Med. 2024 Sep.

. 2024 Sep;26(9):101166.

doi: 10.1016/j.gim.2024.101166. Epub 2024 May 17.

Authors

Collaborators

Undiagnosed Diseases Network:
Maria T Acosta, Margaret Adam, David R Adams, Raquel L Alvarez, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A Ashley, Carlos A Bacino, Guney Bademci, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H Beggs, Edward Behrens, Gill Bejerano, Hugo J Bellen, Jimmy Bennett, Beverly Berg-Rood, Jonathan A Bernstein, Gerard T Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C Briere, Elizabeth A Burke, Lindsay C Burrage, Manish J Butte, Peter Byers, William E Byrd, John Carey, Olveen Carrasquillo, Thomas Cassini, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Ivan Chinn, Gary D Clark, Terra R Coakley, Laurel A Cobban, Joy D Cogan, Matthew Coggins, F Sessions Cole, Heather A Colley, Heidi Cope, Brian Corner, Rosario Corona, William J Craigen, Andrew B Crouse, Michael Cunningham, Precilla D'Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G Dayal, Esteban C Dell'Angelica, Patricia Dickson, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L Doss, Emilie D Douine, Dawn Earl, David J Eckstein, Lisa T Emrick, Christine M Eng, Kimberly Ezell, Marni Falk, Elizabeth L Fieg, Paul G Fisher, Brent L Fogel, Irman Forghani, William A Gahl, Ian Glass, Bernadette Gochuico, Page C Goddard, Rena A Godfrey, Katie Golden-Grant, Alana Grajewski, Don Hadley, Sihoun Hahn, Meghan C Halley, Rizwan Hamid, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M Hisama, Ingrid A Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Sarah Hutchison, Wendy Introne, Rosario Isasi, Kosuke Izumi, Fariha Jamal, Gail P Jarvik, Jeffrey Jarvik, Suman Jayadev, Orpa Jean-Marie, Vaidehi Jobanputra, Lefkothea Karaviti, Shamika Ketkar, Dana Kiley, Gonench Kilich, Shilpa N Kobren, Isaac S Kohane, Jennefer N Kohler, Susan Korrick, Mary Kozuira, Deborah Krakow, Donna M Krasnewich, Elijah Kravets, Seema R Lalani, Byron Lam, Christina Lam, Brendan C Lanpher, Ian R Lanza, Kimberly LeBlanc, Brendan H Lee, Roy Levitt, Richard A Lewis, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K Loo, Joseph Loscalzo, Richard L Maas, Ellen F Macnamara, Calum A MacRae, Valerie V Maduro, AudreyStephannie Maghiro, Rachel Mahoney, May Christine V Malicdan, Laura A Mamounas, Teri A Manolio, Rong Mao, Kenneth Maravilla, Ronit Marom, Gabor Marth, Beth A Martin, Martin G Martin, Julian A Martínez-Agosto, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Alexa T McCray, Elisabeth McGee, Heather Mefford, J Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo Moretti, John Mulvihill, Mariko Nakano-Okuno, Stanley F Nelson, Serena Neumann, John H Newman, Sarah K Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P Orengo, Laura Pace, Stephen Pak, J Carl Pallais, Christina G S Palmer, Jeanette C Papp, Neil H Parker, John A Phillips 3rd, Jennifer E Posey, Lorraine Potocki, Barbara N Pusey Swerdzewski, Aaron Quinlan, Deepak A Rao, Anna Raper, Wendy Raskind, Genecee Renteria, Chloe M Reuter, Lynette Rives, Amy K Robertson, Lance H Rodan, Jill A Rosenfeld, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B Sampson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A Scott, C Ron Scott, Elaine Seto, Vandana Shashi, Jimann Shin, Edwin K Silverman, Janet S Sinsheimer, Kathy Sisco, Edward C Smith, Kevin S Smith, Lilianna Solnica-Krezel, Ben Solomon, Rebecca C Spillmann, Joan M Stoler, Kathleen Sullivan, Jennifer A Sullivan, Angela Sun, Shirley Sutton, David A Sweetser, Virginia Sybert, Holly K Tabor, Queenie K-G Tan, Amelia L M Tan, Arjun Tarakad, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J Tifft, Camilo Toro, Alyssa A Tran, Rachel A Ungar, Tiina K Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P Vogel, Colleen E Wahl, Melissa Walker, Stephanie Wallace, Nicole M Walley, Jennifer Wambach, Jijun Wan, Michael F Wangler, Patricia A Ward, Daniel Wegner, Monika Weisz Hubshman, Mark Wener, Tara Wenger, Monte Westerfield, Matthew T Wheeler, Jordan Whitlock, Lynne A Wolfe, Kim Worley, Changrui Xiao, Shinya Yamamoto, John Yang, Zhe Zhang, Stephan Zuchner

Affiliations

¹ Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA; Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, Stanford, CA. Electronic address: jkohler@stanfordhealthcare.org.
² Department of Obstetrics and Gynecology, MedStar Washington Hospital Center and Georgetown University Hospital, Washington, DC. Electronic address: nicole.legro@gunet.georgetown.edu.
³ Model Organism Screening Center, Department of Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, MO.
⁴ Departments of Neuroscience and of Cell Biology, Yale University School of Medicine, New Haven, CT.
⁵ Department of Chemistry, Washington University in St. Louis, St. Louis, MO; Department of Medicine, Washington University in St. Louis, St. Louis, MO; Center for Proteomics, Metabolomics, and Isotope Tracing, Washington University in St. Louis, St. Louis, MO.
⁶ Department of Genetics, Stanford University School of Medicine, Stanford, CA.
⁷ Department of Pathology, Stanford University School of Medicine, Stanford, CA.
⁸ Invitae, San Francisco, CA.
⁹ Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA.
¹⁰ Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA; Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, Stanford, CA.
¹¹ Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA.
¹² PacBio, 1305 O'Brien Drive Menlo Park, CA.
¹³ Center for Computational Genomics and Data Science, Department of Genetics, University of Alabama, Birmingham, AL.
¹⁴ Department of Genetics, Stanford University School of Medicine, Stanford, CA; Department of Pathology, Stanford University School of Medicine, Stanford, CA.
¹⁵ Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA; Department of Pediatrics, Division of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA.
¹⁶ Institute of Neuroscience, University of Oregon, Eugene, OR.
¹⁷ Departments of Neuroscience and of Cell Biology, Howard Hughes Medical Institute, Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT.

PMID: 38767059
PMCID: PMC11451386 (available on 2025-09-01)
DOI: 10.1016/j.gim.2024.101166

Abstract

Purpose: The function of FAM177A1 and its relationship to human disease is largely unknown. Recent studies have demonstrated FAM177A1 to be a critical immune-associated gene. One previous case study has linked FAM177A1 to a neurodevelopmental disorder in 4 siblings.

Methods: We identified 5 individuals from 3 unrelated families with biallelic variants in FAM177A1. The physiological function of FAM177A1 was studied in a zebrafish model organism and human cell lines with loss-of-function variants similar to the affected cohort.

Results: These individuals share a characteristic phenotype defined by macrocephaly, global developmental delay, intellectual disability, seizures, behavioral abnormalities, hypotonia, and gait disturbance. We show that FAM177A1 localizes to the Golgi complex in mammalian and zebrafish cells. Intersection of the RNA sequencing and metabolomic data sets from FAM177A1-deficient human fibroblasts and whole zebrafish larvae demonstrated dysregulation of pathways associated with apoptosis, inflammation, and negative regulation of cell proliferation.

Conclusion: Our data shed light on the emerging function of FAM177A1 and defines FAM177A1-related neurodevelopmental disorder as a new clinical entity.

Keywords: Developmental Delay; FAM177A1; Macrocephaly; Neurodevelopment; Zebrafish.

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Conflict of interest statement

Conflict of Interest The authors declare no conflicts of interest.

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Loss of function of FAM177A1, a Golgi complex localized protein, causes a novel neurodevelopmental disorder

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Affiliations

Loss of function of FAM177A1, a Golgi complex localized protein, causes a novel neurodevelopmental disorder

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Abstract

Conflict of interest statement

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