P627: Bi-allelic RAB5IF variants associated with craniofacial and skeletal anomalies: Further insights into CFSMR2 syndrome

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.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.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.