Genetic Characterization of PYCR1-Associated De Barsy Syndrome in a Pakistani Family Through Whole Exome Trio Sequencing
Laboratory Genetics and Genomics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
De Barsy Syndrome (DBS), or cutis laxa type IIIB, is a rare autosomal recessive connective tissue disorder predominantly caused by mutations in the PYCR1 gene. It is clinically characterized by progeroid features, cutis laxa, skeletal abnormalities, and multi-system involvement, that mimics other progeroid syndromes, making diagnosis challenging. Here, we present a genetically confirmed case of DBS expanding the phenotypic spectrum and underscoring the utility of whole exome trio sequencing (WES-Trio) in differentiating rare yet overlapping disorders.
Case Presentation
We report a one-day-old male infant born at 34 weeks gestation to a multigenerationally consanguineous family (gravida 6, para 6) via lower segment cesarean section, following a two-week history of oligohydramnios and intrauterine growth restriction. At birth, Apgar scores were 7 and 8 at 1 and 5 minutes, respectively, with anthropometric measurements: weight of 1290g, length of 38cm, and occipital-frontal circumference of 27.5cm. Key clinical features included a progeroid appearance, extensive skin wrinkling, triangular face, large fontanelles, wide cranial sutures, corneal clouding, hyperextensible joints with finger contractures, prominent chest and abdominal veins, bilateral cryptorchidism, and bilateral talipes equinovarus.
Diagnostic Workup
Standard G-banding karyotyping was unremarkable, revealing 46,XY genotype. Initially suspected to have Wiedemann-Rautenstrauch syndrome, the infant underwent genetic testing for POLR3A, which did not reveal pathogenic or likely pathogenic mutations. The case was then referred to a geneticist for further assessment and underwent WES-Trio. Whole blood samples from the proband and parents were collected for DNA extraction and sequencing. Variants were interpreted according to ACMG/AMP guidelines, and structural modeling tools were used to assess the functional impact of variant under investigation.
The proband harbored a likely pathogenic mutation in a homozygous state within exon 6 of PYCR1 (c.752G>A; p.Arg251His). The variant had high pathogenicity scores (REVEL, SIFT, PolyPhen-2), and structural analysis indicated disruption of a salt bridge between Arg251 and Glu246. The genotype-phenotype correlation and the heterozygous carrier status of the parents for this mutation confirmed the diagnosis of DBS.
Treatment and Management
The neonate was admitted to the neonatal intensive care unit immediately post-birth due to respiratory distress, receiving low-flow oxygen (2L/min), which was increased to 4L/min via bCPAP due to increased respiratory effort. Broad-spectrum antibiotics and antifungals were started preemptively to control potential sepsis, and caffeine citrate was administered for apnea of prematurity. Nutritional needs were supported via total parenteral nutrition. A multidisciplinary team, including a neonatologist, pediatric surgeon, orthopedic specialist, and ophthalmologist, was engaged to manage and monitor complications. Early interventions for bilateral talipes equinovarus, such as taping and strapping, were initiated. The family received counseling on the prognosis and home care requirements.
Outcome and Follow-Up
The proband experienced progressive failure to thrive with persistent respiratory and feeding difficulties. Despite supportive care, he passed away on 15th day of life after suffering a massive pulmonary hemorrhage. Genetic counseling was provided to the family to explain recurrence risks and prenatal screening for future pregnancies.
Discussion
This case represents the first genetically confirmed report of DBS in Pakistan. Although a case of DBS was reported in a family of Pakistani origin in 2008, no confirmatory genetic testing was performed. Previous studies have shown that Arg251 is directly involved in stabilization of the inter-homodimer interactions and thus loss of multimerization leads to severe phenotype. Moreover, Arg215His mutation is also reported to correlate with reduced expression of PYCR1 in skin fibroblasts.
Conclusion
In conclusion, this report highlights the clinical and diagnostic complexity of DBS and underscores the value of comprehensive genetic testing, as an essential diagnostic and management tool for rare genetic disorders with phenotypic overlap.
De Barsy Syndrome (DBS), or cutis laxa type IIIB, is a rare autosomal recessive connective tissue disorder predominantly caused by mutations in the PYCR1 gene. It is clinically characterized by progeroid features, cutis laxa, skeletal abnormalities, and multi-system involvement, that mimics other progeroid syndromes, making diagnosis challenging. Here, we present a genetically confirmed case of DBS expanding the phenotypic spectrum and underscoring the utility of whole exome trio sequencing (WES-Trio) in differentiating rare yet overlapping disorders.
Case Presentation
We report a one-day-old male infant born at 34 weeks gestation to a multigenerationally consanguineous family (gravida 6, para 6) via lower segment cesarean section, following a two-week history of oligohydramnios and intrauterine growth restriction. At birth, Apgar scores were 7 and 8 at 1 and 5 minutes, respectively, with anthropometric measurements: weight of 1290g, length of 38cm, and occipital-frontal circumference of 27.5cm. Key clinical features included a progeroid appearance, extensive skin wrinkling, triangular face, large fontanelles, wide cranial sutures, corneal clouding, hyperextensible joints with finger contractures, prominent chest and abdominal veins, bilateral cryptorchidism, and bilateral talipes equinovarus.
Diagnostic Workup
Standard G-banding karyotyping was unremarkable, revealing 46,XY genotype. Initially suspected to have Wiedemann-Rautenstrauch syndrome, the infant underwent genetic testing for POLR3A, which did not reveal pathogenic or likely pathogenic mutations. The case was then referred to a geneticist for further assessment and underwent WES-Trio. Whole blood samples from the proband and parents were collected for DNA extraction and sequencing. Variants were interpreted according to ACMG/AMP guidelines, and structural modeling tools were used to assess the functional impact of variant under investigation.
The proband harbored a likely pathogenic mutation in a homozygous state within exon 6 of PYCR1 (c.752G>A; p.Arg251His). The variant had high pathogenicity scores (REVEL, SIFT, PolyPhen-2), and structural analysis indicated disruption of a salt bridge between Arg251 and Glu246. The genotype-phenotype correlation and the heterozygous carrier status of the parents for this mutation confirmed the diagnosis of DBS.
Treatment and Management
The neonate was admitted to the neonatal intensive care unit immediately post-birth due to respiratory distress, receiving low-flow oxygen (2L/min), which was increased to 4L/min via bCPAP due to increased respiratory effort. Broad-spectrum antibiotics and antifungals were started preemptively to control potential sepsis, and caffeine citrate was administered for apnea of prematurity. Nutritional needs were supported via total parenteral nutrition. A multidisciplinary team, including a neonatologist, pediatric surgeon, orthopedic specialist, and ophthalmologist, was engaged to manage and monitor complications. Early interventions for bilateral talipes equinovarus, such as taping and strapping, were initiated. The family received counseling on the prognosis and home care requirements.
Outcome and Follow-Up
The proband experienced progressive failure to thrive with persistent respiratory and feeding difficulties. Despite supportive care, he passed away on 15th day of life after suffering a massive pulmonary hemorrhage. Genetic counseling was provided to the family to explain recurrence risks and prenatal screening for future pregnancies.
Discussion
This case represents the first genetically confirmed report of DBS in Pakistan. Although a case of DBS was reported in a family of Pakistani origin in 2008, no confirmatory genetic testing was performed. Previous studies have shown that Arg251 is directly involved in stabilization of the inter-homodimer interactions and thus loss of multimerization leads to severe phenotype. Moreover, Arg215His mutation is also reported to correlate with reduced expression of PYCR1 in skin fibroblasts.
Conclusion
In conclusion, this report highlights the clinical and diagnostic complexity of DBS and underscores the value of comprehensive genetic testing, as an essential diagnostic and management tool for rare genetic disorders with phenotypic overlap.