Introduction
Microdeletions of 17p13.3 usually include the gene LIS1 (PAFAH1B1) and present with neuronal migration defects/lissencephaly. However, telomeric microdeletions in this region, which do not include LIS1 but are deleted for YWHAE, are now being recognised as a cause of neurodevelopmental disorder. The YWHAE gene codes for the 14-3-3ϵ protein.Reference Gittenberger-de Groot, Hoppenbrouwers and Miquerol1
In the mouse, 14-3-3ϵ is important for the maturation of the compact ventricular myocardium but haploinsufficiency may cause other cardiac defects. Germline deletion of YWHAE in the mouse resulted in myocardial non-compaction, tricuspid stenosis and atresia, mitral valve abnormalities, and peri-membranous ventricular septal defects.Reference Gittenberger-de Groot, Hoppenbrouwers and Miquerol1,Reference Denommé-Pichon, Collins and Bruel2
CHDs with microdeletions of YWHAE have been reported. One patient out of three had a cardiac defect. Ten out of 27 known cases with this genetic condition also have CHD. These conditions include patent ductus arteriosus (n = 4), patent foramen ovale (n = 2), ventricular septal defect (n = 2), Tetralogy of Fallot (n = 1), and one patient was reported to have a “leaky valve.”3
To the best of our knowledge, this represents the first case of this microdeletion in the context of pulmonary atresia, ventricular septal defect, and discordant ventricular arterial connections with a subsequent extracardiac Fontan palliation.
Case report
The patient presented in the neonatal period with severe cyanosis. He was delivered at term, and five hours after delivery became severely centrally cyanosed. An echocardiogram was performed and showed usual atrial arrangement, concordant atrioventricular arrangement, pulmonary atresia, and absent pulmonary trunk with confluent left and right pulmonary arteries, the aorta arising from the right ventricle, right-sided aortic arch, and a large ventricular septal defect. At one day old, this was surgically palliated with a left modified Blalock–Taussig shunt. In infancy, he presented with increasing cyanosis, with baseline oxygen saturations of between 66 and 72%. Aged 20 months, a right modified Blalock–Taussig shunt was performed; during this procedure, bilateral superior venae cavae were noted. He was followed up through childhood and his exercise tolerance and oxygen saturations did not significantly improve. He underwent fluorescent in situ hybridisation testing aged 4 and was found to be negative for 22q11.2 microdeletion. He attended a mainstream school, was diagnosed with learning difficulties and continued low exercise tolerance. Aged nine, he was transferred to a school for children with special educational needs. He was followed up by the paediatric congenital heart team intermittently due to frequent lack of attendance.
Given his continued low oxygen saturation of 74% and that his weight and height continued to be below 0.4th centile, his case was reviewed. A biventricular repair was not considered suitable due to the aorta arising entirely from the right ventricle and the chords and leaflets of the tricuspid valve being interposed between the aortic valve and the ventricular septal defect, meaning closing the ventricular septal defect and patching the aorta to the left ventricle was not possible. A Mustard repair was also considered unsuitable due to the high associated surgical risk and the resultant systemic right ventricle from the procedure. Therefore, at age 10, he underwent a bidirectional Glenn procedure. This connected his bilateral superior vena cava to the left and right pulmonary arteries, as well as an atrial septectomy and a takedown of his bilateral Blalock–Taussig shunts. Aged 11, he had a completion of total cavo-pulmonary connection with an extra cardiac conduit from his inferior vena cava to his main pulmonary artery.
Aged 19, he was referred to a geneticist who noted bilateral forehead nodules and swollen phalangeal joints. He had epicanthic folds, malar hypoplasia, and a mild ptosis of the left eyelid. There was no history of cleft palate, renal abnormalities, or seizures. He was noted to be of short stature, 156 cm (0.4th centile, −3 SD), with a proportionate weight (51 kg on the 0.4th centile) and head circumference 53.2 cm on the 0.4th centile. Family history showed no other incidents of CHD, but his brother also had learning disabilities, and his mother was of a similar short stature and appearance. There was no available medical history for his father.
Further genetic testing was performed with an array compariative genomic hybridization (CGH) test and revealed a 17p13.3 1.5 Mb terminal microdeletion (1715–1,544,866) and a deletion of unknown significance of chromosome 13q21.2 (60, 439,334–60,623,459) (genome build GRCh37, with 60 kb backbone). The 17p13.3 microdeletion overlapped the 17p13.3 microdeletion syndrome (Miller–Dieker lissencephaly syndrome), but the critical gene for Miller–Dieker syndrome, LIS1 and the PAFAH1B1 genes, were not deleted. Thirty-one genes were deleted in this region, but the only gene listed as an OMIM morbid gene in the heterozygote state was the YWHAE gene. The deletion of uncertain significance of chromosome 13q21.2 included two genes: DIAPH3 and DIAPH3-AS1.
The patient is now 30 years old. He maintains regular follow-up in the adult congenital heart service. His saturations are 93%. He requires support with more complex life issues such as finance and is in receipt of disability benefits, but is otherwise independent and lives with his partner. He is currently stable from a cardiac perspective with good ventricular function and is not on any cardiac medications except aspirin.
Discussion
This case describes an adult with complex CHD who underwent total cavo-pulmonary connection palliation and was found to have 17p13.3 microdeletion involving the YWHAE gene but not LIS1 or PAFAH1B1 genes. Miller–Dieker syndrome may present with associated cardiac abnormalities, which can include ventricular septal defect and conotruncal anomalies.Reference Ueda, Sugiura and Takeshita4 It is of interest to note that there was no deletion of LIS1 or PAFAH1B1 in this patient, and therefore a diagnosis of Miller–Dieker syndrome could not be made. Currently, the CHD morphologies in conjunction with 17p13.3 microdeletion reported in the literature include Tetralogy of Fallot,Reference Chen, Liu and Lin5 ventricular septal defect,Reference Bruno, Anderlid and Lindstrand6 patent ductus arteriosus,Reference Nagamani, Zhang and Shchelochkov7 and patent foramen ovale.Reference Schiff, Delahaye and Andrieux8
A review of patients on DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER)Reference Foreman9 found 19 patients reported with deletions of the YWHAE gene, with deletions up to 10 Mb. Eighteen of the 19 patients had short stature. Six had a patent ductus arteriosus, six had ventricular septal defects, four had an atrial septal defect, three with pulmonary stenosis, two had tricuspid stenosis, and three were reported as having abnormal heart morphology. No cases of pulmonary atresia were reported.
What is important to note in this case is the initial negative result of the fluorescent in situ hybridisation test. One previous case report of a foetus with Tetralogy of Fallot also reported a negative initial fluorescent in situ hybridisation test and then subsequent positive 17p13.3 microdeletion result.Reference Ueda, Sugiura and Takeshita4 22q11.2 microdeletion is commonly associated with Tetralogy of Fallot.Reference Silversides, Lionel and Costain10 Historically, only fluorescent in situ hybridisation testing was done when there was a clinical suspicion of an underlying 22q11.2 microdeletion. In cases for adult patients where there are historical negative fluorescent in situ hybridisation results, but there is still a strong suspicion of an underlying genetic issue, repeat genetic testing with array CGH could be considered.
Patients who undergo a total cavo-pulmonary connection palliation are predicted to have an overall shorter life expectancy and many potential complications.Reference Diller, Kempny and Alonso-Gonzalez11 However, the patient has lived well into adulthood, is stable from a cardiac perspective, and has a good degree of independence. This is an overall and very positive outcome that may be useful to clinicians counselling parents of children with a similar diagnosis.
Conclusion
In conclusion, we present here a case of an adult patient with pulmonary atresia, ventricular septal defect, and discordant ventricular arterial connections with subsequent total cavo-pulmonary connection palliation and a chromosome 17p13.3 microdeletion involving the YWHAE but not LIS1 or PAFAH1B1 gene. It is hoped that this case will add to the existing knowledge surrounding this genetic condition and CHD to inform other clinicians.
Financial support
This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.
Competing interests
The authors declare none.
Ethical standard
Consent for this case study to be written and published was gained from the patient and a copy of the report has been shared with them.
