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.of the central nervous system, which include developmental delay, intellectual disability (ID), learning disabilities, autism spectrum disorders, motor and tic disorders, and communication disorders. 2 NDD can be accompanied by non-central nervous system defects, e.g., congenital heart defects (CHD) and facial dysmorphism, in a

A novel TBX5 mutation predisposes to familial cardiac septal defects and atrial fibrillation as well as bicuspid aortic valve

“…The well-established environmental factors underlying CHD include maternal conditions (such as innutrition, viral infection and endocrine disorder) and exposures to toxic chemicals, therapeutic drugs, or ionizing radiation during pregnancy (Patel and Burns, 2013). However, increasing studies underscore the genetic defects underpinning CHD, and variations in over 70 genes, encompassing those encoding transcription factors, signaling molecules, and sarcomeric proteins, have been involved in CHD (Bashamboo et al, 2018;Cantù et al, 2018;Jaouadi et al, 2018;Li et al, 2018a,c;Lombardo et al, 2018;Manheimer et al, 2018;Pierpont et al, 2018;Razmara and Garshasbi, 2018;Stephen et al, 2018;Xu et al, 2018;Yu Z et al, 2018;Alankarage et al, 2019;Gao et al, 2019;Kalayinia et al, 2019Kalayinia et al, , 2020Ma et al, 2019;Wang J et al, 2019, Wang Z et al, 2019Watkins et al, 2019;Zhu et al, 2019;Faucherre et al, 2020;Shabana et al, 2020;Zhao et al, 2020). Among the recognized CHD-causative genes, the majority code for cardiac transcription factors, encompassing TBX5, GATA4, and NKX2-5 (Li and Yang, 2017).…”

Fetal Anomalies Associated with Novel Pathogenic Variants in TMEM94

“…It is well known that gene defects in many members of the transmembrane protein family, such as TMEM138 [ 9 ], TMEM165 [ 10 ], TMEM231 [ 11 ], TMEM237 [ 12 ], TMEM67 [ 13 ], and TMEM5 [ 14 ] are associated with fetal anomalies. TMEM94 defects have been reported with a prenatal history of omphalocele, atrioventricular septal defect (AVSD), and intestinal malrotation, which was surgically corrected after birth in a Turkish patient aged 24 years of age [ 1 ]. The previous report also included three families with Arabian ancestry (from Oman, Qatar, and Egypt).…”

“…In both families, cardiac abnormality was the obvious structural irregularity identified by antenatal ultrasound. The loss of function variants detected in these two fetuses are correlated to the cardiac abnormality phenotype observed in the mouse model [ 1 ]. The identification of these two novel mutations increases the spectrum of pathogenic variants in TMEM94 that associated with IDDCDF.…”

“…Neurodevelopmental disorders are genetically and phenotypically heterogeneous conditions and can be accompanied by congenital heart defects and dysmorphic features. Intellectual developmental disorder with cardiac defects and dysmorphic facies (IDDCDF, MIM 618316) is a recently described neurodevelopmental disorder, which is characterized by global developmental delay, intellectual disability and speech delay, congenital cardiac malformations, and dysmorphic facial features [ 1 ]. It was initially reported in ten patients from six unrelated families with an autosomal recessive pattern of inheritance.…”

“…TMEM94 was mapped to chromosome 17q25.1 [ 2 ] and consisted of 31 coding exons (RefSeq NM_014738), which encoded for an uncharacterized transmembrane nuclear protein. In a murine model, homozygous loss of TMEM94 was embryonically lethal and led to craniofacial defects, cardiac abnormalities, and abnormal neuronal migration in the central nervous system that mimicked human phenotype [ 1 ]. To date, all of the seven mutations in TMEM94 were predicted to result in truncated proteins lacking the highly conserved C-terminal domain and showed significantly decreased TMEM94 expression [ 1 ].…”