Bi-allelic RAB5IF Variants Associated with Craniofacial and Skeletal Anomalies: Further Insights into CFSMR2 Syndrome
Clinical Genetics and Therapeutics
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Health Services and Implementation
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Primary Categories:
- Clinical Genetics
- Health services and Implementation
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Secondary Categories:
- Clinical Genetics
- Health services and Implementation
Introduction:
In the United States, rare disease (RD) is defined as a condition, which affects fewer than 200,000 individuals, or about 1 in 1,600 people in the current population. Globally, approximately 300 million affected individuals worldwide, RDs are a leading cause of child mortality and disability in high-income countries. However, collectively, there are about 7,000 of these disorders affecting 6–8% of the US population, representing a significant public health and socioeconomic cost. Beyond the medical, financial, and emotional burdens faced by patients, the full scope of RDs remains unclear, with estimates suggesting over 8,000 conditions exist. People living with rare diseases often struggle for years before receiving an accurate diagnosis, and often remain undiagnosed for a decade or longer. The diagnostic odyssey often includes many clinical visits, medical testing that is sometimes invasive, and possible incorrect diagnoses. Furthermore, even with a diagnosis only about 5 percent of rare diseases have approved treatments. Established in January 2020, the Undiagnosed Rare Disease Clinic (URDC) is a multidisciplinary center dedicated to offering genetic diagnoses for patients and families navigating the uncertainty of undiagnosed rare diseases. In September 2023, URDC has been designated as Indiana University Diagnostic Center of excellence as clinical site of Undiagnosed disease network (UDN).
Methods:
The URDC team enroll only those patients which have been suffering from genetic disorder and are undiagnosed even after extensive genetic testing. Upon enrollment, patient samples are collected during clinic visits for reanalysis, including exome sequencing (ES), research-based genome sequencing (GS), RNA sequencing (RNA-Seq), and targeted metabolomic testing. Clinically negative exome sequencing (ES) data is reanalyzed periodically and GS data is analyzed to identify the causative variant in non-coding regions, mitochondrial, STR and Copy number alterations (CNV) that are usually not captured by ES. The RNA-Seq data is analyzed to validate splice-altering variants.
Results:
Out of 133 enrolled patients, 110 cases have been analyzed resulted in 17 solved 7 possibly solved cases, with approximately 20% diagnostic rate. The remaining undiagnosed patients present a unique opportunity for further research and novel gene discovery. The team developed multi-site collaborations with various research and clinical groups to study the functional effect of genes and variant candidates. The teamwork of URDC is especially important in the state of Indiana as it has been markedly underserved regarding genetic services. Thankfully, URDC can provide this specialty care and serve health disparities populations everywhere.
Conclusion:
In conclusion, we describe the experience of URDC, the analytical strategy and the results obtained in the last 4 years, experience, and learned lessons with URDC as relate to ultra-rare disease patients. We summarize the results of this pilot project and emphasize the importance of a sustainable institutional URDC program.
Introduction
The RAB5IF gene (C20orf24, MIM: 616994) encodes an assembly factor associated with mitochondrial respirasome formation, oxygen consumption, and ATP production. Recently, RAB5IF has been linked to craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-2 (CFSMR2). Here, we describe four new cases with bi-allelic loss-of-function variants in RAB5IF.
Case Presentation
A 2-year-old male with global developmental delay, hypotonia, dysmorphic features—including midface retrusion, macrocephaly, wide nasal bridge, and hypertelorism—recurrent infections, delayed dental eruption, short stature, rib fusion, scoliosis, and bilateral fifth finger clinodactyly was evaluated at the Undiagnosed Rare Disease Clinic (URDC) at Indiana University School of Medicine.
Diagnostic Workup
Prior to URDC enrollment, clinical exome sequencing (CES) and chromosomal microarray analysis (CMA) were negative. Research-based genome sequencing, identified compound heterozygous variants [c.215_217del p.(Ala72del); c.348+1G>T] in RAB5IF (NM_018840.5)
Treatment and Management
The CFSMR2 is a recently identified syndrome, currently, no potential therapy or treatment is available for individuals affected with CFSMR2 but potential pregnancy risk can be known in the family following the diagnosis of the patient.
Outcome and Follow-Up
Following identifying the first patient with RAB5IF variants, we identified two additional patients with similar features who harbor biallelic loss-of-function variants in RAB5IF through GeneMatcher. Patient 1 and his sibling, presenting with global developmental delay, skeletal abnormalities, renal anomalies, and dysmorphic features similar to our index case, harbor a homozygous nonsense variant c.138C>A p.(Tyr46Ter). The second patient, presenting with global delay, hypotonia, skeletal abnormalities, and a facial gestalt similar to the other patients, carries a whole-gene deletion (seq[GRCh38] del(20)(q11.23q11.23); NC_000020.11:g.36,601,386_36,620,327del) in trans with a heterozygous loss-of-function variant c.125del p.(Leu42Ter) in RAB5IF. All the variants are predicted to be loss of function mutations.
Discussion
In this study, we identified bi-allelic variants in RAB5IF in four patients with features characteristic of CFSMR2, including hypotonia, neurodevelopmental delay, a distinctive facial gestalt, and skeletal malformations. RAB5IF was recently linked to Craniofacial Dysmorphism, Skeletal Anomalies, and Impaired Intellectual Development Syndrome-2 (CFSMR2). Recent studies show that RAB5IF functionally interacts with the TMCO1 protein, which is associated with Craniofacial Dysmorphism, Skeletal Anomalies, and Impaired Intellectual Development Syndrome-1 (CFSMR1). The two proteins dimerize, and the loss of RAB5IF leads to a near-complete loss of TMCO1 protein, suggesting their interdependence and a possible role of ER-mitochondria interaction in CFSMR pathophysiology. To date, only one patient with bi-allelic RAB5IF variants has been documented with CFSMR2 syndrome (PMID: 35614220).
Conclusion
Our findings expand the phenotypic and genotypic spectrum of RAB5IF-associated CFSMR2, providing additional evidence for this gene's role in the syndrome. This research supports the recognition of RAB5IF as a contributor to a newly recognizable syndrome, furthering our understanding of its clinical and molecular characteristics.
In the United States, rare disease (RD) is defined as a condition, which affects fewer than 200,000 individuals, or about 1 in 1,600 people in the current population. Globally, approximately 300 million affected individuals worldwide, RDs are a leading cause of child mortality and disability in high-income countries. However, collectively, there are about 7,000 of these disorders affecting 6–8% of the US population, representing a significant public health and socioeconomic cost. Beyond the medical, financial, and emotional burdens faced by patients, the full scope of RDs remains unclear, with estimates suggesting over 8,000 conditions exist. People living with rare diseases often struggle for years before receiving an accurate diagnosis, and often remain undiagnosed for a decade or longer. The diagnostic odyssey often includes many clinical visits, medical testing that is sometimes invasive, and possible incorrect diagnoses. Furthermore, even with a diagnosis only about 5 percent of rare diseases have approved treatments. Established in January 2020, the Undiagnosed Rare Disease Clinic (URDC) is a multidisciplinary center dedicated to offering genetic diagnoses for patients and families navigating the uncertainty of undiagnosed rare diseases. In September 2023, URDC has been designated as Indiana University Diagnostic Center of excellence as clinical site of Undiagnosed disease network (UDN).
Methods:
The URDC team enroll only those patients which have been suffering from genetic disorder and are undiagnosed even after extensive genetic testing. Upon enrollment, patient samples are collected during clinic visits for reanalysis, including exome sequencing (ES), research-based genome sequencing (GS), RNA sequencing (RNA-Seq), and targeted metabolomic testing. Clinically negative exome sequencing (ES) data is reanalyzed periodically and GS data is analyzed to identify the causative variant in non-coding regions, mitochondrial, STR and Copy number alterations (CNV) that are usually not captured by ES. The RNA-Seq data is analyzed to validate splice-altering variants.
Results:
Out of 133 enrolled patients, 110 cases have been analyzed resulted in 17 solved 7 possibly solved cases, with approximately 20% diagnostic rate. The remaining undiagnosed patients present a unique opportunity for further research and novel gene discovery. The team developed multi-site collaborations with various research and clinical groups to study the functional effect of genes and variant candidates. The teamwork of URDC is especially important in the state of Indiana as it has been markedly underserved regarding genetic services. Thankfully, URDC can provide this specialty care and serve health disparities populations everywhere.
Conclusion:
In conclusion, we describe the experience of URDC, the analytical strategy and the results obtained in the last 4 years, experience, and learned lessons with URDC as relate to ultra-rare disease patients. We summarize the results of this pilot project and emphasize the importance of a sustainable institutional URDC program.
Introduction
The RAB5IF gene (C20orf24, MIM: 616994) encodes an assembly factor associated with mitochondrial respirasome formation, oxygen consumption, and ATP production. Recently, RAB5IF has been linked to craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-2 (CFSMR2). Here, we describe four new cases with bi-allelic loss-of-function variants in RAB5IF.
Case Presentation
A 2-year-old male with global developmental delay, hypotonia, dysmorphic features—including midface retrusion, macrocephaly, wide nasal bridge, and hypertelorism—recurrent infections, delayed dental eruption, short stature, rib fusion, scoliosis, and bilateral fifth finger clinodactyly was evaluated at the Undiagnosed Rare Disease Clinic (URDC) at Indiana University School of Medicine.
Diagnostic Workup
Prior to URDC enrollment, clinical exome sequencing (CES) and chromosomal microarray analysis (CMA) were negative. Research-based genome sequencing, identified compound heterozygous variants [c.215_217del p.(Ala72del); c.348+1G>T] in RAB5IF (NM_018840.5)
Treatment and Management
The CFSMR2 is a recently identified syndrome, currently, no potential therapy or treatment is available for individuals affected with CFSMR2 but potential pregnancy risk can be known in the family following the diagnosis of the patient.
Outcome and Follow-Up
Following identifying the first patient with RAB5IF variants, we identified two additional patients with similar features who harbor biallelic loss-of-function variants in RAB5IF through GeneMatcher. Patient 1 and his sibling, presenting with global developmental delay, skeletal abnormalities, renal anomalies, and dysmorphic features similar to our index case, harbor a homozygous nonsense variant c.138C>A p.(Tyr46Ter). The second patient, presenting with global delay, hypotonia, skeletal abnormalities, and a facial gestalt similar to the other patients, carries a whole-gene deletion (seq[GRCh38] del(20)(q11.23q11.23); NC_000020.11:g.36,601,386_36,620,327del) in trans with a heterozygous loss-of-function variant c.125del p.(Leu42Ter) in RAB5IF. All the variants are predicted to be loss of function mutations.
Discussion
In this study, we identified bi-allelic variants in RAB5IF in four patients with features characteristic of CFSMR2, including hypotonia, neurodevelopmental delay, a distinctive facial gestalt, and skeletal malformations. RAB5IF was recently linked to Craniofacial Dysmorphism, Skeletal Anomalies, and Impaired Intellectual Development Syndrome-2 (CFSMR2). Recent studies show that RAB5IF functionally interacts with the TMCO1 protein, which is associated with Craniofacial Dysmorphism, Skeletal Anomalies, and Impaired Intellectual Development Syndrome-1 (CFSMR1). The two proteins dimerize, and the loss of RAB5IF leads to a near-complete loss of TMCO1 protein, suggesting their interdependence and a possible role of ER-mitochondria interaction in CFSMR pathophysiology. To date, only one patient with bi-allelic RAB5IF variants has been documented with CFSMR2 syndrome (PMID: 35614220).
Conclusion
Our findings expand the phenotypic and genotypic spectrum of RAB5IF-associated CFSMR2, providing additional evidence for this gene's role in the syndrome. This research supports the recognition of RAB5IF as a contributor to a newly recognizable syndrome, furthering our understanding of its clinical and molecular characteristics.