1. De Barsy Syndrome type B presenting with cardiac and genitourinary abnormalities
Dutta AK1, Thomas N2, Ekbote A1, Omprakash S1, Danda S1
1Department of Clinical Genetics and 2Department of Neonatology,
Christian Medical College, Vellore, India

2. PURPOSE
To describe a child with genetically proven De Barsy syndrome type B.
To highlight the cardiac and genitourinary abnormalities in the index child which had not been documented in earlier reports.
To showcase the utility of clinical exome sequencing in the molecular confirmation of rare inherited disorders in a cost effective manner.
To present the putative biologic effect of the detected mutation.

3. BACKGROUND
De Barsy Syndrome type B (ICD – 10 Q87.7, OMIM ) is a rare cutis laxa syndrome with progeroid appearance due to a defect in Pyrroline-5- Carboxylate Reductase (PYCR1) gene.
Pyrroline-5-carboxylate reductase (EC ) catalyses the NAD(P)H-dependent conversion of pyrroline-5-carboxylate to proline.
PYCR1 deficiency leads to an altered mitochondrial membrane potential (MMP), an increased fragmentation of the mitochondrial network and higher apoptosis rates upon oxidative stress.
Prevalence: <1/ 10,00,000, Inheritance: Autosomal recessive, Age of onset: Infancy, neonatal
Less than 100 cases reported so far , three from India (Dimopoulou et al).

4. CASE REPORT
A female preterm neonate, first born to fifth degree consanguineously married parents was admitted under department of Neonatology.
Concerns: prematurity, intra uterine growth restriction and loose skin folds

5. Table 1- Clinical features (up to three months of follow up)
Clinical features in decreasing frequency
(after Dimopoulou et al)
Features in the index case
Wrinkled skin
Present
Joint hyperlaxity
Typical facial gestalt
Present (figure 1)
IUGR
Psychomotor retardation
Under follow up
Osteopenia
Present (figure 2)
Thin/ translucent skin
Microcephaly
Postnatal growth delay
Wormian bones
Not evaluated
Hypotonia
Late Fontanel closure
Finger contractures
Hernias
Absent
Blue sclera
Strabismus
Athetoid movements
Cataract / corneal clouding
*Cardiac anomalies
Aneurysmal dilatation of inter-atrial septum
*Genitourinary anomalies
Enlargement of clitoris
*Not described previously

6. CLINICAL PHOTOGRAPH
Figure 1

7. INFANTOGRAM
Figure 2

8. METHODS OF GENETIC CONFIRMATION
Based on the presenting features De Barsy syndrome type A (ALDH18A1 gene related) or type B (PYCR1 gene related) were suspected.
As the genetic aetiology of a proportion of children with De Barsy syndrome remains to be delineated, clinical exome sequencing was planned.
Clinical exome sequencing was performed in a commercial laboratory with Illumina MiSeq platform using TruSight One Sequencing kit.
Variants were analysed with VariantStudio software.
Putative pathological variant was confirmed by Sanger sequencing in Clinical Genetics Laboratory, Christian Medical College, Vellore.
Both the parents were screened for carrier status.
The effect of the pathogenic variant was analyzed with Mutationtaster software.

9. RESULT AND DISCUSSION
Clinical exome sequencing revealed a homozygous variant C > T/T (GRCh37, location chr17: C>T, cDNA.799G>A, R119H) (Figure 3).
This is a known pathological variant (rs ) associated with De Barsy Syndrome type B (Reversade et al).
The mutation was confirmed by Sanger sequencing in Clinical Genetics Department, Christian Medical College, Vellore and both the parents were found to carry the mutation in heterozygous state (Figure 4).

10. RESULTS
Figure 3
Figure 4

11. RESULTS
This substitution leads to gain of a donor splice site (CCAC|tgca) inside exon 4, which will lead to the loss of 116th to 121st amino acids and the downstream amino acids might also get lost.
This variant was previously functionally characterized and showed to abolish the expression of PYCR1 protein in cultured fibroblasts from affected patient (Reversade et al).

12. Discussion
As De Barsy syndrome have two implicated genes (ALDH18A1 and PYCR1) and has overlapping features with other Autosomal Recessive Cutis Laxa syndromes (Fibulin-5, EFEMP2 , LTBP4, GORAB, ATP6V0A2 gene related) genetic confirmation is necessary.
Clinical exome sequencing is a powerful diagnostic tool for cost effective genetic diagnosis however the low coverage and read depth are the limitations necessitating confirmation by Sanger sequencing.
Being an Autosomal Recessive disorder this disease has a 25% recurrence risk in future pregnancies . Genetic diagnosis also paves the way for the option prenatal diagnosis for the family.

13. Conclusion
Here we have described a child with De Barsy Syndrome type B who presented with cardiac and genitourinary anomalies which were not documented in earlier reports.

14. References
1. Dimopoulou A, Fischer B, Gardeitchik T, Schröter P, Kayserili H, Schlack C, et al. Genotype–phenotype spectrum of PYCR1 related autosomal recessive cutis laxa. Molecular genetics and metabolism ;110(3):352–61.
2. Reversade B, Escande-Beillard N, Dimopoulou A, Fischer B, Chng SC, Li Y, et al. Mutations in PYCR1 cause cutis laxa with progeroid features. Nature Genetics Sep;41(9):1016–21.

15. Acknowledgements
The parents of the affected child for their kind consent.
Dr Gautham Arunachal U, Clinical Genetics Unit, CMC Vellore.
Genotypic Technology

16. Thank you