Identification of a Novel Homozygous TMEM53 Variant in a Patient with Extensive Homozygosity:Classification Challenges Despite Phenotypic Consistency with Craniotubular Dysplasia
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction:
The identification and classification of genetic variants in consanguineous populations, where extensive regions of homozygosity are common, can provide valuable insight into rare disease associations but remains challenging as it adds complexity to the interpretation of identified variants. TMEM53 is a gene with emerging links to clinical phenotypes, although its role in disease remains largely underexplored. Here, we report the discovery of a novel homozygous TMEM53 (c.704G>T) variant in a consanguineous patient who presents with clinical features aligning with those associated with TMEM53-related disease in the literature and corroborated by OMIM. This variant lies within a 65 MB region of homozygosity, with an overall autozygosity encompassing 12% of the patient’s exome, consistent with a recessive inheritance model often seen in consanguineous populations.
Methods:
The patient is a 57-year-old male from a consanguineous Iranian family who presented with calvarial hyperostosis, vision loss, joint laxity and a personal and family history of short stature. Clinical exome sequencing was performed, revealing the TMEM53 (c.704G>T) variant within a significant homozygous region leading to a predicted p.Arg235Ser amino acid substitution. Computational tools were employed to predict the variant’s impact, while comparative genomics, clinical databases and OMIM data were reviewed to assess its potential pathogenicity. Population frequency data were reviewed, and a detailed clinical evaluation was conducted to correlate observed symptoms with those reported in OMIM and case reports in the literature for TMEM53-associated disease.
Results:
The patient’s clinical presentation aligns closely with the phenotype associated with TMEM53 in OMIM, Craniotubular dysplasia, Ikegawa type [MIM: 619727]. However, despite the exceptional phenotypic overlap, classifying the variant beyond a variant of uncertain significance (VUS) remains challenging. The novel TMEM53 (c.704G>T) variant is absent from population databases and has not been reported in the literature. Computational predictions and conservation analyses provide inconclusive evidence regarding pathogenicity further complicating pathogenic assessment. Literature review highlights a scarcity of functional studies on TMEM53, with existing case reports offering preliminary evidence of a disease association. An additional challenge in classifying this variant arises from the nature of reported TMEM53 variants in the literature, which are predominantly loss-of-function mutations, with only one reported missense variant found in trans with a 54 base-pair in-frame deletion.
Conclusion:
This case underscores the complexities involved in variant classification within consanguineous populations, where large regions of homozygosity can suggest potential pathogenic variants. Despite a strong phenotypic correlation with OMIM descriptions, the absence of functional data and limited case studies make it difficult to elevate this TMEM53 variant beyond a VUS classification. Further research is needed, including functional assays and segregation studies, to clarify the role of TMEM53 in disease and to refine classification criteria for variants in understudied genes. This case highlights the importance of integrating clinical phenotype with genetic findings and the challenges inherent in the classification of variants within consanguineous populations.
The identification and classification of genetic variants in consanguineous populations, where extensive regions of homozygosity are common, can provide valuable insight into rare disease associations but remains challenging as it adds complexity to the interpretation of identified variants. TMEM53 is a gene with emerging links to clinical phenotypes, although its role in disease remains largely underexplored. Here, we report the discovery of a novel homozygous TMEM53 (c.704G>T) variant in a consanguineous patient who presents with clinical features aligning with those associated with TMEM53-related disease in the literature and corroborated by OMIM. This variant lies within a 65 MB region of homozygosity, with an overall autozygosity encompassing 12% of the patient’s exome, consistent with a recessive inheritance model often seen in consanguineous populations.
Methods:
The patient is a 57-year-old male from a consanguineous Iranian family who presented with calvarial hyperostosis, vision loss, joint laxity and a personal and family history of short stature. Clinical exome sequencing was performed, revealing the TMEM53 (c.704G>T) variant within a significant homozygous region leading to a predicted p.Arg235Ser amino acid substitution. Computational tools were employed to predict the variant’s impact, while comparative genomics, clinical databases and OMIM data were reviewed to assess its potential pathogenicity. Population frequency data were reviewed, and a detailed clinical evaluation was conducted to correlate observed symptoms with those reported in OMIM and case reports in the literature for TMEM53-associated disease.
Results:
The patient’s clinical presentation aligns closely with the phenotype associated with TMEM53 in OMIM, Craniotubular dysplasia, Ikegawa type [MIM: 619727]. However, despite the exceptional phenotypic overlap, classifying the variant beyond a variant of uncertain significance (VUS) remains challenging. The novel TMEM53 (c.704G>T) variant is absent from population databases and has not been reported in the literature. Computational predictions and conservation analyses provide inconclusive evidence regarding pathogenicity further complicating pathogenic assessment. Literature review highlights a scarcity of functional studies on TMEM53, with existing case reports offering preliminary evidence of a disease association. An additional challenge in classifying this variant arises from the nature of reported TMEM53 variants in the literature, which are predominantly loss-of-function mutations, with only one reported missense variant found in trans with a 54 base-pair in-frame deletion.
Conclusion:
This case underscores the complexities involved in variant classification within consanguineous populations, where large regions of homozygosity can suggest potential pathogenic variants. Despite a strong phenotypic correlation with OMIM descriptions, the absence of functional data and limited case studies make it difficult to elevate this TMEM53 variant beyond a VUS classification. Further research is needed, including functional assays and segregation studies, to clarify the role of TMEM53 in disease and to refine classification criteria for variants in understudied genes. This case highlights the importance of integrating clinical phenotype with genetic findings and the challenges inherent in the classification of variants within consanguineous populations.