A Case Report: Expanding the Phenotypic Spectrum of EIF5A-Related Neurodevelopmental Disorder
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
First described in 2021, EIF5A-related neurodevelopmental disorder (OMIM #619376), also referred to as Faundes-Banka syndrome (FABAS), is an autosomal dominant disorder caused by heterozygous mutation in the EIF5A gene on chromosome 17p13. EIF5A gene encodes the eukaryotic translation initiation factor 5A, a translation elongation factor important for protein synthesis and cell proliferation. Only seven individuals with this syndrome have been described in the medical literature thus far.
FABAS is associated with variable symptoms of developmental delay, microcephaly, congenital anomalies, facial dysmorphism, and eye abnormalities. Here, we present an eighth case involving a novel heterozygous missense variant, presenting with primary microcephaly, mild gross motor delay, high myopia, and vertical nystagmus that had not been previously described in this condition.
Case Presentation
The proband is an 18-month-old female evaluated for microcephaly and mild motor delays. She is the first and only child of healthy, nonconsanguineous parents, conceived through in vitro fertilization. Born at 40 weeks gestation, she was noted to have microcephaly and a cardiac ventricular septal defect. She presents with borderline-mild gross motor delays: rolling over at 6 months, crawling at 12 months, and walking at 18 months. Fine motor, speech, and social development milestones were appropriate. Physical examination revealed dysmorphic features, including down-slanting palpebral fissures and a left ear pit. Brain MRI was normal, except for mildly symmetrically enlarged ocular globes. Ophthalmologic evaluation identified high myopia, vertical nystagmus, and right-eye exotropia.
Diagnostic Workup
Chromosomal microarray analysis (CMA) was non-diagnostic. Trio exome sequencing identified a de novo heterozygous likely pathogenic variant (NM_001970.4 c.334 C>T; p.(L112F)) in exon 4 of EIF5A. This variant was not observed in large population databases (gnomAD). In silico analysis suggests that this missense variant is deleterious to protein structure and function. Trio exome sequencing also revealed a secondary finding in PALB2 (NM_024675.3 c.940 C>T; p.(Gln314Ter)) in both the proband and her father; however, this finding is unlikely to contribute to the proband’s clinical phenotype.
Conclusion
Patients who were previously reported displayed phenotypic variability. Microcephaly was observed in four of the seven patients, and all exhibited developmental delays ranging from mild to severe, with motor and speech delays noted in three patients. Cardiac anomalies were identified in three patients: atrial septal defect, dysplastic tricuspid valve with regurgitation, and bicuspid aortic valve.
Our patient presented with overlapping features, including mild motor delays, primary microcephaly, and cardiac ventricular septal defect. Vertical nystagmus was not reported previously. Interestingly, in DECIPHER there is one patient (#2346) with approximately 286Kb deletion that includes EIF5A and clinical presentation that includes nystagmus. Yet, this individual’s deletion includes additional genes. With so few cases reported, further research is essential to expand our understanding as we characterize this newly discovered genetic condition involving the EIF5A gene.
First described in 2021, EIF5A-related neurodevelopmental disorder (OMIM #619376), also referred to as Faundes-Banka syndrome (FABAS), is an autosomal dominant disorder caused by heterozygous mutation in the EIF5A gene on chromosome 17p13. EIF5A gene encodes the eukaryotic translation initiation factor 5A, a translation elongation factor important for protein synthesis and cell proliferation. Only seven individuals with this syndrome have been described in the medical literature thus far.
FABAS is associated with variable symptoms of developmental delay, microcephaly, congenital anomalies, facial dysmorphism, and eye abnormalities. Here, we present an eighth case involving a novel heterozygous missense variant, presenting with primary microcephaly, mild gross motor delay, high myopia, and vertical nystagmus that had not been previously described in this condition.
Case Presentation
The proband is an 18-month-old female evaluated for microcephaly and mild motor delays. She is the first and only child of healthy, nonconsanguineous parents, conceived through in vitro fertilization. Born at 40 weeks gestation, she was noted to have microcephaly and a cardiac ventricular septal defect. She presents with borderline-mild gross motor delays: rolling over at 6 months, crawling at 12 months, and walking at 18 months. Fine motor, speech, and social development milestones were appropriate. Physical examination revealed dysmorphic features, including down-slanting palpebral fissures and a left ear pit. Brain MRI was normal, except for mildly symmetrically enlarged ocular globes. Ophthalmologic evaluation identified high myopia, vertical nystagmus, and right-eye exotropia.
Diagnostic Workup
Chromosomal microarray analysis (CMA) was non-diagnostic. Trio exome sequencing identified a de novo heterozygous likely pathogenic variant (NM_001970.4 c.334 C>T; p.(L112F)) in exon 4 of EIF5A. This variant was not observed in large population databases (gnomAD). In silico analysis suggests that this missense variant is deleterious to protein structure and function. Trio exome sequencing also revealed a secondary finding in PALB2 (NM_024675.3 c.940 C>T; p.(Gln314Ter)) in both the proband and her father; however, this finding is unlikely to contribute to the proband’s clinical phenotype.
Conclusion
Patients who were previously reported displayed phenotypic variability. Microcephaly was observed in four of the seven patients, and all exhibited developmental delays ranging from mild to severe, with motor and speech delays noted in three patients. Cardiac anomalies were identified in three patients: atrial septal defect, dysplastic tricuspid valve with regurgitation, and bicuspid aortic valve.
Our patient presented with overlapping features, including mild motor delays, primary microcephaly, and cardiac ventricular septal defect. Vertical nystagmus was not reported previously. Interestingly, in DECIPHER there is one patient (#2346) with approximately 286Kb deletion that includes EIF5A and clinical presentation that includes nystagmus. Yet, this individual’s deletion includes additional genes. With so few cases reported, further research is essential to expand our understanding as we characterize this newly discovered genetic condition involving the EIF5A gene.