Clinical Spectrum of Autosomal Recessive Spliceosomal Gene CWC27 Variants
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction
Pathogenic homozygous and compound heterozygous variants disrupting the spliceosomal gene CWC27 lead to a spectrum of conditions extending from isolated retinal degeneration to severe syndromic forms that can include: short stature, failure to thrive (FTT), craniofacial abnormalities, skeletal anomalies, developmental delays, and ectodermal dysplasia changes.
Here we describe a patient who presented with features of ectodermal dysplasia, retinitis pigmentosa and preserved intellect diagnosed with CWC27-associated spliceosomeopathy. This report further expands the phenotype of this condition by adding a patient from Hispanic background and a syndromic form with no intellectual disability.
Case Presentation
We report a 19-year-old female born with multiple congenital anomalies including proportional short stature of prenatal onset; FTT; dysmorphic features including blepharophimosis and mild ptosis; bilateral retinal degeneration; and ectodermal findings including almost complete absence of eyebrows and eyelashes, frontal sparse hair, dry skin, dysplastic toenails, and hypodontia. The patient also presented with hallux valgus bilaterally, multiple nevi and a large hypopigmented flat lesion in the posterior right leg.
Her development and intellect were all within normal limits.
She is the first child born to a non-consanguineous couple of Mexican descend. The patient's parents were both born in a small town with under 300 habitants.
Diagnostic Workup
Exome sequencing resulted in two pathogenic homozygous variants c.1002del: p.(Val335Ter) in exon 11 of the CWC27 gene, inherited one from each unaffected parent.
Treatment and Management
The patient was diagnosed with rod cone dystrophy during her teen years when her vision was compromised. She is currently undergoing mobility training and learning Braille to address her severe vision loss.
Outcome and Follow-Up
Following her molecular diagnosis a series of evaluations were ordered. A consultation with a retina specialist was completed and long term follow-up established. An echocardiogram and cardiac exam were done and revealed a normal anatomy. A renal ultrasound was normal. The was referred for an Endocrine consultation which revealed short stature with a normal pituitary axis, except for an elevated prolactin level.
Discussion
CWC27-associated spliceosomeopathy has characteristics that are not shared with other Spliceosomopathies. It is the only one inherited in an autosomal recessive manner and the only spliceosomopathy that, in its syndromic form, mixes and overlaps phenotypes of other spliceosomal genes which usually present with a predominant phenotype of either isolated retinitis pigmentosa (PRPF3, PRPF31, PRPF4, SNRNP200) or craniofacial and skeletal developmental defects (EFTUD2, SF3B4, TXNL4A, RBM8A, SNRPB, EIF4A3). The N-terminal CWC27 truncations seem to be associated with more severe phenotypes while frameshift variants in the C-terminal region of the protein exhibit a milder phenotype. Our patient had a change in the C-terminal region and expressed a full phenotype and no intellectual disability.
Conclusion
We suggest an early clinical suspicion of this condition in children with ectodermal dysplasia and short stature of prenatal onset. We also propose including the CWC27 gene in the current ectodermal dysplasia panels given that its early diagnosis allows identification of medically actionable recommendations such as consultation with a retinal specialist. Further research on the complexity of the spliceosome could allow for targeted therapies to preserve vision in this patient population.
Pathogenic homozygous and compound heterozygous variants disrupting the spliceosomal gene CWC27 lead to a spectrum of conditions extending from isolated retinal degeneration to severe syndromic forms that can include: short stature, failure to thrive (FTT), craniofacial abnormalities, skeletal anomalies, developmental delays, and ectodermal dysplasia changes.
Here we describe a patient who presented with features of ectodermal dysplasia, retinitis pigmentosa and preserved intellect diagnosed with CWC27-associated spliceosomeopathy. This report further expands the phenotype of this condition by adding a patient from Hispanic background and a syndromic form with no intellectual disability.
Case Presentation
We report a 19-year-old female born with multiple congenital anomalies including proportional short stature of prenatal onset; FTT; dysmorphic features including blepharophimosis and mild ptosis; bilateral retinal degeneration; and ectodermal findings including almost complete absence of eyebrows and eyelashes, frontal sparse hair, dry skin, dysplastic toenails, and hypodontia. The patient also presented with hallux valgus bilaterally, multiple nevi and a large hypopigmented flat lesion in the posterior right leg.
Her development and intellect were all within normal limits.
She is the first child born to a non-consanguineous couple of Mexican descend. The patient's parents were both born in a small town with under 300 habitants.
Diagnostic Workup
Exome sequencing resulted in two pathogenic homozygous variants c.1002del: p.(Val335Ter) in exon 11 of the CWC27 gene, inherited one from each unaffected parent.
Treatment and Management
The patient was diagnosed with rod cone dystrophy during her teen years when her vision was compromised. She is currently undergoing mobility training and learning Braille to address her severe vision loss.
Outcome and Follow-Up
Following her molecular diagnosis a series of evaluations were ordered. A consultation with a retina specialist was completed and long term follow-up established. An echocardiogram and cardiac exam were done and revealed a normal anatomy. A renal ultrasound was normal. The was referred for an Endocrine consultation which revealed short stature with a normal pituitary axis, except for an elevated prolactin level.
Discussion
CWC27-associated spliceosomeopathy has characteristics that are not shared with other Spliceosomopathies. It is the only one inherited in an autosomal recessive manner and the only spliceosomopathy that, in its syndromic form, mixes and overlaps phenotypes of other spliceosomal genes which usually present with a predominant phenotype of either isolated retinitis pigmentosa (PRPF3, PRPF31, PRPF4, SNRNP200) or craniofacial and skeletal developmental defects (EFTUD2, SF3B4, TXNL4A, RBM8A, SNRPB, EIF4A3). The N-terminal CWC27 truncations seem to be associated with more severe phenotypes while frameshift variants in the C-terminal region of the protein exhibit a milder phenotype. Our patient had a change in the C-terminal region and expressed a full phenotype and no intellectual disability.
Conclusion
We suggest an early clinical suspicion of this condition in children with ectodermal dysplasia and short stature of prenatal onset. We also propose including the CWC27 gene in the current ectodermal dysplasia panels given that its early diagnosis allows identification of medically actionable recommendations such as consultation with a retinal specialist. Further research on the complexity of the spliceosome could allow for targeted therapies to preserve vision in this patient population.