Bi-allelic TMEM94 Truncating Variants Are Associated with Neurodevelopmental Delay, Congenital Heart Defects, and Distinct Facial Dysmorphism

Undiagnosed Diseases Network members

Research output: Contribution to journalArticle

Abstract

Neurodevelopmental disorders (NDD) are genetically and phenotypically heterogeneous conditions due to defects in genes involved in development and function of the nervous system. Individuals with NDD, in addition to their primary neurodevelopmental phenotype, may also have accompanying syndromic features that can be very helpful diagnostically especially those with recognizable facial appearance. In this study, we describe ten similarly affected individuals from six unrelated families of different ethnic origins having bi-allelic truncating variants in TMEM94, which encodes for an uncharacterized transmembrane nuclear protein that is highly conserved across mammals. The affected individuals manifested with global developmental delay/intellectual disability, and dysmorphic facial features including triangular face, deep set eyes, broad nasal root and tip and anteverted nostrils, thick arched eye brows, hypertrichosis, pointed chin, and hypertelorism. Birthweight in the upper normal range was observed in most, and all but one had congenital heart defects (CHD). Gene expression analysis in available cells from affected individuals showed reduced expression of TMEM94. Global transcriptome profiling using microarray and RNA sequencing revealed several dysregulated genes essential for cell growth, proliferation and survival that are predicted to have an impact on cardiotoxicity hematological system and neurodevelopment. Loss of Tmem94 in mouse model generated by CRISPR/Cas9 was embryonic lethal and led to craniofacial and cardiac abnormalities and abnormal neuronal migration pattern, suggesting that this gene is important in craniofacial, cardiovascular, and nervous system development. Our study suggests the genetic etiology of a recognizable dysmorphic syndrome with NDD and CHD and highlights the role of TMEM94 in early development.

Original languageEnglish
Pages (from-to)948-967
Number of pages20
JournalAmerican Journal of Human Genetics
Volume103
Issue number6
DOIs
Publication statusPublished - 06-12-2018

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Congenital Heart Defects
Nervous System
Clustered Regularly Interspaced Short Palindromic Repeats
Craniofacial Abnormalities
Hypertrichosis
Hypertelorism
RNA Sequence Analysis
Chin
Meristem
Essential Genes
Gene Expression Profiling
Nuclear Proteins
Cardiovascular System
Nose
Intellectual Disability
Genes
Mammals
Cell Survival
Reference Values
Cell Proliferation

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

@article{ea9f180a723f436ca1574c33561c7311,
title = "Bi-allelic TMEM94 Truncating Variants Are Associated with Neurodevelopmental Delay, Congenital Heart Defects, and Distinct Facial Dysmorphism",
abstract = "Neurodevelopmental disorders (NDD) are genetically and phenotypically heterogeneous conditions due to defects in genes involved in development and function of the nervous system. Individuals with NDD, in addition to their primary neurodevelopmental phenotype, may also have accompanying syndromic features that can be very helpful diagnostically especially those with recognizable facial appearance. In this study, we describe ten similarly affected individuals from six unrelated families of different ethnic origins having bi-allelic truncating variants in TMEM94, which encodes for an uncharacterized transmembrane nuclear protein that is highly conserved across mammals. The affected individuals manifested with global developmental delay/intellectual disability, and dysmorphic facial features including triangular face, deep set eyes, broad nasal root and tip and anteverted nostrils, thick arched eye brows, hypertrichosis, pointed chin, and hypertelorism. Birthweight in the upper normal range was observed in most, and all but one had congenital heart defects (CHD). Gene expression analysis in available cells from affected individuals showed reduced expression of TMEM94. Global transcriptome profiling using microarray and RNA sequencing revealed several dysregulated genes essential for cell growth, proliferation and survival that are predicted to have an impact on cardiotoxicity hematological system and neurodevelopment. Loss of Tmem94 in mouse model generated by CRISPR/Cas9 was embryonic lethal and led to craniofacial and cardiac abnormalities and abnormal neuronal migration pattern, suggesting that this gene is important in craniofacial, cardiovascular, and nervous system development. Our study suggests the genetic etiology of a recognizable dysmorphic syndrome with NDD and CHD and highlights the role of TMEM94 in early development.",
author = "{Undiagnosed Diseases Network members} and Joshi Stephen and Sateesh Maddirevula and Sheela Nampoothiri and Burke, {John D.} and Matthew Herzog and Anju Shukla and Katharina Steindl and Ascia Eskin and Patil, {Siddaramappa J.} and Pascal Joset and Hane Lee and Garrett, {Lisa J.} and Tadafumi Yokoyama and Nicholas Balanda and Bodine, {Steven P.} and Tolman, {Nathanial J.} and Zerfas, {Patricia M.} and Allison Zheng and Georgia Ramantani and Girisha, {Katta M.} and Cecilia Rivas and Suresh, {Pujar V.} and Abdel Elkahloun and Alsaif, {Hessa S.} and Wakil, {Salma M.} and Laila Mahmoud and Rehab Ali and Michaela Prochazkova and Kulkarni, {Ashok B.} and Tawfeg Ben-Omran and Dilek Colak and Morris, {H. Douglas} and Anita Rauch and Martinez-Agosto, {Julian A.} and Nelson, {Stanley F.} and Alkuraya, {Fowzan S.} and Gahl, {William A.} and Malicdan, {May Christine V.}",
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Bi-allelic TMEM94 Truncating Variants Are Associated with Neurodevelopmental Delay, Congenital Heart Defects, and Distinct Facial Dysmorphism. / Undiagnosed Diseases Network members.

In: American Journal of Human Genetics, Vol. 103, No. 6, 06.12.2018, p. 948-967.

Research output: Contribution to journalArticle

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AU - Undiagnosed Diseases Network members

AU - Stephen, Joshi

AU - Maddirevula, Sateesh

AU - Nampoothiri, Sheela

AU - Burke, John D.

AU - Herzog, Matthew

AU - Shukla, Anju

AU - Steindl, Katharina

AU - Eskin, Ascia

AU - Patil, Siddaramappa J.

AU - Joset, Pascal

AU - Lee, Hane

AU - Garrett, Lisa J.

AU - Yokoyama, Tadafumi

AU - Balanda, Nicholas

AU - Bodine, Steven P.

AU - Tolman, Nathanial J.

AU - Zerfas, Patricia M.

AU - Zheng, Allison

AU - Ramantani, Georgia

AU - Girisha, Katta M.

AU - Rivas, Cecilia

AU - Suresh, Pujar V.

AU - Elkahloun, Abdel

AU - Alsaif, Hessa S.

AU - Wakil, Salma M.

AU - Mahmoud, Laila

AU - Ali, Rehab

AU - Prochazkova, Michaela

AU - Kulkarni, Ashok B.

AU - Ben-Omran, Tawfeg

AU - Colak, Dilek

AU - Morris, H. Douglas

AU - Rauch, Anita

AU - Martinez-Agosto, Julian A.

AU - Nelson, Stanley F.

AU - Alkuraya, Fowzan S.

AU - Gahl, William A.

AU - Malicdan, May Christine V.

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N2 - Neurodevelopmental disorders (NDD) are genetically and phenotypically heterogeneous conditions due to defects in genes involved in development and function of the nervous system. Individuals with NDD, in addition to their primary neurodevelopmental phenotype, may also have accompanying syndromic features that can be very helpful diagnostically especially those with recognizable facial appearance. In this study, we describe ten similarly affected individuals from six unrelated families of different ethnic origins having bi-allelic truncating variants in TMEM94, which encodes for an uncharacterized transmembrane nuclear protein that is highly conserved across mammals. The affected individuals manifested with global developmental delay/intellectual disability, and dysmorphic facial features including triangular face, deep set eyes, broad nasal root and tip and anteverted nostrils, thick arched eye brows, hypertrichosis, pointed chin, and hypertelorism. Birthweight in the upper normal range was observed in most, and all but one had congenital heart defects (CHD). Gene expression analysis in available cells from affected individuals showed reduced expression of TMEM94. Global transcriptome profiling using microarray and RNA sequencing revealed several dysregulated genes essential for cell growth, proliferation and survival that are predicted to have an impact on cardiotoxicity hematological system and neurodevelopment. Loss of Tmem94 in mouse model generated by CRISPR/Cas9 was embryonic lethal and led to craniofacial and cardiac abnormalities and abnormal neuronal migration pattern, suggesting that this gene is important in craniofacial, cardiovascular, and nervous system development. Our study suggests the genetic etiology of a recognizable dysmorphic syndrome with NDD and CHD and highlights the role of TMEM94 in early development.

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