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 language | English |
|---|---|
| Pages (from-to) | 948-967 |
| Number of pages | 20 |
| Journal | American Journal of Human Genetics |
| Volume | 103 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 06-12-2018 |
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All Science Journal Classification (ASJC) codes
- Genetics
- Genetics(clinical)
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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 journal › Article
TY - JOUR
T1 - Bi-allelic TMEM94 Truncating Variants Are Associated with Neurodevelopmental Delay, Congenital Heart Defects, and Distinct Facial Dysmorphism
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.
PY - 2018/12/6
Y1 - 2018/12/6
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85057471722&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85057471722&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2018.11.001
DO - 10.1016/j.ajhg.2018.11.001
M3 - Article
C2 - 30526868
AN - SCOPUS:85057471722
VL - 103
SP - 948
EP - 967
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 6
ER -