New Insights into TMEM147-Related Neurodevelopmental Disorders: A Case Report and Literature Review
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In regions characterized by high consanguinity, such as Libya, the prevalence of autosomal recessive genetic disorders is expected to be more pronounced than in outbred populations [1]. The link between neurodevelopmental disorders and genetic abnormalities is critical, as many such conditions result from specific genetic variants or chromosomal alterations that disrupt normal brain development [2]. The transmembrane protein 147 (TMEM147) gene (MIM: 613585), located at 19q13.12, encodes a highly conserved integral membrane protein consisting of 224 amino acids and seven transmembrane domains [3]. TMEM147 is vital for neurodevelopment because it contributes to protein biogenesis and localization within cellular structures such as the endoplasmic reticulum and nuclear envelope. It also regulates key molecular pathways during early embryonic development, particularly the Nodal signaling pathway, which is essential for mesodermal induction and neural patterning [3,4]. Furthermore, TMEM147 interacts significantly with the C-terminal domain of the lamin B receptor, thereby influencing heterochromatin organization and cholesterol biosynthesis [5,6].
Neurodevelopmental disorder with facial dysmorphism, absent language, and pseudo-Pelger-Huet Anomaly (NEDFLPH) is an autosomal recessive condition characterized by global developmental delay and severely impaired intellectual development. NEDFLPH is a newly characterized and under-documented disorder, reflecting a gap in our comprehensive understanding of its implications. To date, only two studies have explored the involvement of the TMEM147 gene in the pathogenic mechanisms underlying NEDFLPH. In the initial study, Thomas et al. [7] examined a cohort of 23 individuals harboring 12 distinct variants in the TMEM147 gene, with all affected subjects exhibiting a constellation of clinical features that define the NEDFLPH phenotype. In a subsequent study, Ghorashi et al. [8] identified a novel variant in the TMEM147 gene in two patients with intellectual disability, thereby providing further evidence for the pathogenic role of TMEM147 mutations in intellectual disability and highlighting spasticity as a new phenotypic manifestation alongside previously recognized characteristics.
Here, we present a case involving a 10-month-old female patient with developmental delay, intellectual disability, speech delay, and facial dysmorphism. The diagnosis of NEDFLPH was confirmed by whole-exome sequencing, which revealed a novel pathogenic variant in the TMEM147 gene.
A 10-month-old girl was hospitalized with a severe lower respiratory tract infection and viral-induced wheezing. She was born at term (3.0 kg at birth) without perinatal complications to healthy, consanguineous Libyan parents. She has four older healthy siblings (three brothers and one sister), and the family history is negative for birth defects, developmental delay, intellectual disability, or other neurological disorders (Fig. 1). During her examination by a pediatric neurologist, the child’s anthropometric measurements were as follows: weight 7 kg (7th centile), height 66.5 cm (<3rd centile), and head circumference 41 cm (3rd centile). These measurements, consistent with previous growth data, indicate a significant developmental delay. Brain magnetic resonance imaging revealed partial dysgenesis of the corpus callosum, with no remarkable findings or defects in myelination.
Family pedigree and segregation analysis of the identified variant.
At 10 months, the child demonstrates significant delays in achieving essential milestones, particularly in motor and socio-emotional development. Specifically, she is unable to sit independently, does not engage in finger-feeding, and cannot voluntarily grasp objects. Additionally, her social interactions are limited; she does not smile or vocalize in response to verbal cues, although spontaneous smiling is observed. Her laughter is infrequent and lacks volume. Notably, she exhibits a lack of object permanence and fails to respond when her name is called. There are no attempts to imitate sounds or facial expressions, and she does not engage in vocal play or babbling, despite having a normal hearing assessment. As shown in Fig. 2, the child displays distinctive dysmorphic facial features, including a coarse face, synophrys, an everted lower lip vermilion, a wide mouth with a tented upper lip vermilion, a smooth long philtrum, a wide nasal bridge, low-set ears, telecanthus, bushy eyebrows, and a low anterior hairline. Echocardiographic screening confirmed the presence of a hemodynamically insignificant atrial septal defect.
Dysmorphic facial features in the transmembrane protein 147 (TMEM147) affected child.
The coding exons of over 20,000 genes were enriched using KAPA sequence capture technology (Roche, Basel, Switzerland) and sequenced on an Illumina platform (next-generation sequencing; San Diego, CA, USA). Filtering was applied for X-linked, autosomal, and recessive inheritance patterns. The analysis identified a homozygous variant, c.398T>A p.(Ile133Asn), in the TMEM147 gene (OMIM: *613585), thereby confirming the diagnosis of NEDFLPH.
The identification of the homozygous missense variant c.398T>A p.(Ile133Asn) in the TMEM147 gene (OMIM: *613585), coupled with the supportive phenotypic characteristics observed in our patient, confirms the diagnosis of NEDFLPH. This variant represents the first documented case in Libya and is among the rare occurrences identified worldwide. It is classified as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar), and its allele frequency in the general population has not been documented.
Although the precise mechanism remains unclear, this variant is thought to induce steric conflicts with adjacent amino acids due to the replacement of thymine (T) with adenine (A) at position 398 of the TMEM147 coding sequence, thereby disrupting the protein’s normal conformation and function. The substitution results in the replacement of isoleucine (Ile) with asparagine (Asn) at position 133, which impairs the chemical and physical stability of the TMEM147 protein. This alteration contributes to overall protein dysfunction and adversely affects its role in maintaining nuclear envelope integrity and proper endoplasmic reticulum function. Given that TMEM147 is highly expressed during brain development and plays a crucial role in regulatory pathways governing gene expression, the presence of this variant may disrupt these pathways and lead to abnormal neuronal differentiation and connectivity [7].
This variant has already been identified in nine patients from five distinct families. Notably, one of these families resides in France but has North African ancestry, while the remaining families originate from Egypt. The affected individuals exhibited a consistent combination of clinical features that define the NEDFLPH phenotype, including developmental delay, intellectual disability, and facial dysmorphism [7]. Our findings align with these observations regarding the clinical presentation associated with the detected missense variant in the TMEM147 gene (Table 1), suggesting that this variant should be considered in the differential diagnosis of chromatinopathies. This underscores the importance of recognizing the diverse phenotypic manifestations associated with TMEM147 variants and their overlap with other genetic disorders. However, we did not observe the pseudo-Pelger-Huet anomaly, as evidenced by the normal results of the cytological examination of our patient’s blood smear. It is noteworthy that in the cited study, not all patients exhibited this hematological anomaly; it is suggested that this feature is more relevant in cases involving TMEM147 null alleles [7,8]. This indicates that while some patients may present with this specific hematological finding, it is not necessarily observed in all individuals with TMEM147-related neurodevelopmental disorders.
Phenotypic comparison: current case findings and previous reports
This case represents the first reported instance in Libya and adds to the rare global occurrences associated with TMEM147 mutations. Further functional studies are essential to elucidate the molecular mechanisms by which the c.398T>A p.(Ile133Asn) variant and other relevant mutations impact protein stability, function, and cellular processes. Additionally, establishing databases that compile clinical, genetic, and functional data on TMEM147-related disorders could enhance collaborative research and pave the way for potential therapeutic strategies.
Verbal and written informed consent were obtained from the parents for the publication of clinical details and related images of their child. The study was approved by the Libyan National Committee for Biosafety and Bioethics at the Faculty of Medical Technology, Misurata University (013.H.24.1). The genetic analysis presented in this study was conducted at the Bioscientia Institute for Medical Diagnostics GmbH in Germany. Data generated during this study are available upon reasonable request from the corresponding author.
Notes
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Author contribution
Conceptualization: AAA and SMA. Data curation: AAA. Project administration: BMA. Visualization: AAA. Writing - original draft: BMA. Writing - review & editing: AAA and SMA.