10p12.1p11.21 microdeletion including WAC and ZEB1: A case report and literature review
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
To date, 14 individuals have been reported in the literature with large deletions of chromosome 10p12.1p11.21. We describe a male patient with a novel heterozygous deletion of chromosome 10p12.1p11.21 that includes the WAC and ZEB1 genes. Heterozygous loss-of-function variants in WAC are associated with DeSanto-Shinawi syndrome (DESSH), characterized by neonatal hypotonia, feeding problems, variable degrees of developmental delay and/or intellectual disability, behavioral differences, and describable features. Respiratory abnormalities have been reported in approximately 40% of individuals, including recurrent infections, asthma, and abnormal breathing patterns. Reported MRI findings include ventriculomegaly, white matter abnormalities, and corpus callosum and cerebellum abnormalities. Less common features include seizures, obesity, hearing loss, and kidney problems. Heterozygous pathogenic variants in ZEB1 are associated with corneal dystrophy. Individuals with 10p11p12 deletions involving the WAC gene share a common phenotype with DESSH, but may also have a Dandy-Walker malformation, severe sensorineural hearing loss and/or chronic respiratory failure requiring long-term oxygen, which are features not well described in the literature yet. This case report adds to the literature by expanding the phenotypic spectrum of deletions of chromosome 10p12.1p11.21.
Case Presentation
Our patient was seen at 10 days old with concerns for Dandy-Walker malformation in the context of mild ventriculomegaly, increasing echogenicity of the periventricular white matter and bilateral basal ganglia, large ventricular septal defect (VSD), large patent ductus arteriosus and suspected pneumonia. Overall, the pregnancy was unremarkable with imaging at 32 weeks showing dilated cerebral ventricles and a fetal MRI at 35 weeks consistent with Dandy-Walker malformation. Prenatal cell-free DNA was low risk and diagnostic testing was declined. The patient was delivered via C-section at 35 2/7 weeks due to concerns for partial placental abruption and non-reassuring fetal heart tones, with a birth weight of 5 lb 9.2 oz, length of 45.7 cm, and head circumference of 32 cm. In addition to an abnormal postnatal brain MRI and VSD, the patient’s admission was further complicated by dysphagia, a bilateral inguinal hernia, and chronic respiratory failure with multiple failed extubations requiring respiratory support. He was discharged home at 5 months old with G-tube dependence and home oxygen.
Diagnostic Workup
A chromosomal microarray identified an approximately 8.15 Mb deletion of chromosome 10p12.1p11.21 (GRCh37: 28624088-36777045), classified as a pathogenic copy number variant. The deletion included 20 OMIM genes, of which 2 are associated with an autosomal dominant phenotype in humans (WAC, ZEB1).
Treatment and Management
There were no specific treatment recommendations, but screening recommendations included: Neurology follow-up for possible seizure activity; Ophthalmology assessment for possible cortical visual impairment, strabismus, refractive errors, and corneal dystrophy; Audiology assessment for hearing abnormalities; Cardiology follow-up for congenital heart defects, Pulmonology follow-up for respiratory support; Gastroenterology follow-up for feeding problems; and renal ultrasound for kidney anomalies.
Outcome and Follow-Up
The patient was seen by Genetics at 7 months old for revaluation. At follow-up, the patient's ongoing concerns included global developmental delays, severe to profound bilateral hearing loss, and ongoing respiratory support with home oxygen. He was also enrolled into early intervention services, including developmental, occupational, and speech therapy and continues to follow with the Neurology, Ophthalmology, ENT and Cardiology teams.
Discussion
Our patient’s medical history is consistent with a 10p12.1p11.21 microdeletion. Brain anomalies have been previously reported for 10p12.1p11.21 microdeletions; however, Dandy-Walker malformations have yet to be described as part of the spectrum of clinical features. In addition, our patient also had much more pronounced sensorineural hearing loss and respiratory difficulties compared to other reported cases in the literature. This unique case expands on the known clinical phenotype in the brain and highlights a more severe clinical phenotype involving hearing and respiratory abnormalities.
Conclusion
Microdeletions of 10p12.1p11.21 are very uncommon. Overall, our patient’s presentation is more severe than previously reported cases in the literature. This study expands the phenotypic spectrum of deletions of chromosome 10p12.1p11.21.
To date, 14 individuals have been reported in the literature with large deletions of chromosome 10p12.1p11.21. We describe a male patient with a novel heterozygous deletion of chromosome 10p12.1p11.21 that includes the WAC and ZEB1 genes. Heterozygous loss-of-function variants in WAC are associated with DeSanto-Shinawi syndrome (DESSH), characterized by neonatal hypotonia, feeding problems, variable degrees of developmental delay and/or intellectual disability, behavioral differences, and describable features. Respiratory abnormalities have been reported in approximately 40% of individuals, including recurrent infections, asthma, and abnormal breathing patterns. Reported MRI findings include ventriculomegaly, white matter abnormalities, and corpus callosum and cerebellum abnormalities. Less common features include seizures, obesity, hearing loss, and kidney problems. Heterozygous pathogenic variants in ZEB1 are associated with corneal dystrophy. Individuals with 10p11p12 deletions involving the WAC gene share a common phenotype with DESSH, but may also have a Dandy-Walker malformation, severe sensorineural hearing loss and/or chronic respiratory failure requiring long-term oxygen, which are features not well described in the literature yet. This case report adds to the literature by expanding the phenotypic spectrum of deletions of chromosome 10p12.1p11.21.
Case Presentation
Our patient was seen at 10 days old with concerns for Dandy-Walker malformation in the context of mild ventriculomegaly, increasing echogenicity of the periventricular white matter and bilateral basal ganglia, large ventricular septal defect (VSD), large patent ductus arteriosus and suspected pneumonia. Overall, the pregnancy was unremarkable with imaging at 32 weeks showing dilated cerebral ventricles and a fetal MRI at 35 weeks consistent with Dandy-Walker malformation. Prenatal cell-free DNA was low risk and diagnostic testing was declined. The patient was delivered via C-section at 35 2/7 weeks due to concerns for partial placental abruption and non-reassuring fetal heart tones, with a birth weight of 5 lb 9.2 oz, length of 45.7 cm, and head circumference of 32 cm. In addition to an abnormal postnatal brain MRI and VSD, the patient’s admission was further complicated by dysphagia, a bilateral inguinal hernia, and chronic respiratory failure with multiple failed extubations requiring respiratory support. He was discharged home at 5 months old with G-tube dependence and home oxygen.
Diagnostic Workup
A chromosomal microarray identified an approximately 8.15 Mb deletion of chromosome 10p12.1p11.21 (GRCh37: 28624088-36777045), classified as a pathogenic copy number variant. The deletion included 20 OMIM genes, of which 2 are associated with an autosomal dominant phenotype in humans (WAC, ZEB1).
Treatment and Management
There were no specific treatment recommendations, but screening recommendations included: Neurology follow-up for possible seizure activity; Ophthalmology assessment for possible cortical visual impairment, strabismus, refractive errors, and corneal dystrophy; Audiology assessment for hearing abnormalities; Cardiology follow-up for congenital heart defects, Pulmonology follow-up for respiratory support; Gastroenterology follow-up for feeding problems; and renal ultrasound for kidney anomalies.
Outcome and Follow-Up
The patient was seen by Genetics at 7 months old for revaluation. At follow-up, the patient's ongoing concerns included global developmental delays, severe to profound bilateral hearing loss, and ongoing respiratory support with home oxygen. He was also enrolled into early intervention services, including developmental, occupational, and speech therapy and continues to follow with the Neurology, Ophthalmology, ENT and Cardiology teams.
Discussion
Our patient’s medical history is consistent with a 10p12.1p11.21 microdeletion. Brain anomalies have been previously reported for 10p12.1p11.21 microdeletions; however, Dandy-Walker malformations have yet to be described as part of the spectrum of clinical features. In addition, our patient also had much more pronounced sensorineural hearing loss and respiratory difficulties compared to other reported cases in the literature. This unique case expands on the known clinical phenotype in the brain and highlights a more severe clinical phenotype involving hearing and respiratory abnormalities.
Conclusion
Microdeletions of 10p12.1p11.21 are very uncommon. Overall, our patient’s presentation is more severe than previously reported cases in the literature. This study expands the phenotypic spectrum of deletions of chromosome 10p12.1p11.21.