958 Biallelic variants in TTC21B as a rare cause of early-onset arterial hypertension and tubuloglomerular kidney disease

Aims

Recent advances in gene sequencing technology have catapulted the field of genetic medicine from database collection into an information processing and pattern recognition era. With more and more strong-association genes being linked to specific diseases, the next hurdle lies in identifying genetic causes for rarer, less well-defined syndromes where the uncertain phenotypic spectrum obscures potential genetic candidates. Here, we investigate the cause of extreme early-onset hypertension and kidney disease in a pair of affected siblings, demonstrating the need for a wider gene panel for diagnosing early-onset hypertension.

Methods

The index case and her sibling underwent comprehensive clinical, imaging and histological testing for possible causes of hypertension and kidney disease. This was followed by genetic tests, starting with a massively parallel sequencing (MPS) limited panel testing for monogenic causes of arterial hypertension. We then performed whole genome sequencing (WGS) as part of the Genomics England 100,000 Genomes Project and applied a 26-gene virtual panel for ‘extreme early-onset hypertension’. Subsequently, we reviewed the 100,000 Genomes Project rare disease data for other patients recruited under this extreme early-onset hypertension phenotype. A literature review was performed to identify any previous studies linking TTC21B mutations and hypertension. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project; http://www.genomicsengland.co.uk.

Results

The proband (table 1, II.1) was a 3.5-year-old girl presenting with severe hypertension, proteinuria, kidney failure, left ventricular hypertrophy, liver enzyme abnormalities, and growth retardation. Kidney ultrasound scans showed bilateral small kidneys with a loss of corticomedullary differentiation. Kidney biopsy showed sclerosed glomeruli, severe tubular atrophy with tubulointerstitial fibrosis in addition to arteriolar changes secondary to systemic hypertension. Her sibling (table 1, II.2), presented similarly with severe hypertension and kidney failure. Both the MPS panel testing and WGS virtual panel for early-onset hypertension yielded no pathogenic variants. Manual curation of WGS data finally revealed a heterozygous nonsense variant p.(Gln834Ter) in conjunction with a heterozygous missense variant p.(Pro209Leu) in TTC21B, both of which were predicted to be pathogenic according to the ACMG criteria. This was not identified earlier as TTC21B was not present in the severe hypertension gene panel. Literature review showed that biallelic variants in TTC21B have been associated with nephronophthisis (NPHP) and Jeune asphyxiating thoracic dystrophy, both of which are ciliopathies, but also with focal segmental glomerulosclerosis (FSGS), a glomerular kidney disease. During this search, there was a notable incidence (57%) of hypertension out of the 56 total cases, 84% of which aligned with a p.(Pro209Leu) variant. Searching the Genomics England 100,000 Genomes Project revealed one additional case of arterial hypertension associated with biallelic TTC21B variants.

Conclusion

In conclusion, biallelic variants in TTC21B have been shown to produce a wide spectrum of kidney phenotypes, resembling both NPHP and FSGS. This mixed tubulointerstitial and glomerular disease can often present with early-onset hypertension, and the diagnosis may be overlooked due to the lack of typical ciliopathy features. The addition of TTC21B to the early-onset hypertension gene panels can ensure a timelier genetic diagnosis for this rare tubuloglomerular kidney disease (figure 1).