Telomere biology disorder prevalence and phenotypes in adults with familial hematologic and/or pulmonary presentations

Abstract

Telomere biology disorders (TBDs) present heterogeneously, ranging from infantile bone marrow failure associated with very short telomeres to adult-onset interstitial lung disease (ILD) with normal telomere length. Yield of genetic testing and phenotypic spectra for TBDs caused by the expanding list of telomere genes in adults remain understudied. Thus, we screened adults aged ≥18 years with a personal and/or family history clustering hematologic disorders and/or ILD enrolled on The University of Chicago Inherited Hematologic Disorders Registry for causative variants in 13 TBD genes. Sixteen (10%) of 153 probands carried causative variants distributed among TERT (n = 6), TERC (n = 4), PARN (n = 5), or RTEL1 (n = 1), of which 19% were copy number variants. The highest yield (9 of 22 [41%]) was in families with mixed hematologic and ILD presentations, suggesting that ILD in hematology populations and hematologic abnormalities in ILD populations warrant TBD genetic testing. Four (3%) of 117 familial hematologic disorder families without ILD carried TBD variants, making TBD second to only DDX41 in frequency for genetic diagnoses in this population. Phenotypes of 17 carriers with heterozygous PARN variants included 4 (24%) with hematologic abnormalities, 67% with lymphocyte telomere lengths measured by flow cytometry and fluorescence in situ hybridization at or above the 10th percentile, and a high penetrance for ILD. Alternative etiologies for cytopenias and/or ILD such as autoimmune features were noted in multiple TBD families, emphasizing the need to maintain clinical suspicion for a TBD despite the presence of alternative explanations.

Telomere biology disorders

“… Gene mutation Product Inheritance Disease and phenotype Frequency Comment TERT 5 – 7 , 17 , 47 , 50 , 54 , 59 TERT Autosomal dominant Autosomal recessive DC a IPF b /FIP c AA d /MDS e Familial Liver Cirrhosis DC HHS f 15–25% 8–15% (familial) 1–3% (sporadic) 3–5% (AA) 20% (familial MDS-AML i ) Rare, unknown Rare TERT and TERC mutations are the most common TBD mutations and present later in life. TERC 5 , 6 , 20 , 47 , 50 , 54 , 59 Telomerase RNA component Autosomal dominant DC IPF/FIP AA/MDS Familial Liver Cirrhosis 10% 8–15% (familial) 1–3% (sporadic) 3–5% (AA) 20% (familial MDS-AML) rare, unknown TERT and TERC mutations are the most common TBD mutations and present later in life. DKC1 10 , 48 Dyskerin X-linked recessive DC HHS IPF/FIP 15–25% rare <1% Described in severe X-linked DC, which presents in the first decade of life RTEL1 19 , 29 , 50 RTEL1 Autosomal recessive Autosomal dominant DC HHS IPF/FIP Rare Rare 5–10% – TINF2 16 , 49 ...…”

“…Other haematological conditions described in TBD include macrocytosis, isolated cytopenias, paroxysmal nocturnal haemoglobinuria and essential thrombocythaemia 5 , 6 , 8 , 15 , 20 , 54 (Fig. 5 ).…”

“…Up to 40% of patients with TBD have liver involvement 6 , 58 , 59 . Manifestations include transaminitis, non-alcoholic steatohepatitis, nodular regenerative hyperplasia, cryptogenic liver cirrhosis, noncirrhotic portal hypertension and HPS (Fig.…”

“…Manifestations include transaminitis, non-alcoholic steatohepatitis, nodular regenerative hyperplasia, cryptogenic liver cirrhosis, noncirrhotic portal hypertension and HPS (Fig. 5 ) 6 , 58 – 60 . Biopsy findings include inflammatory and fibrotic components, hepatic nodular regeneration, cirrhosis and idiopathic hemosiderosis 58 – 60 .…”

“…DC accounts for less than 5% of all TBD and has an estimated incidence of 1 in 1,000,000 8 . It is estimated that 41% of familial mixed haematologic and interstitial lung disease (ILD) and 3% of familial haematologic disorders are due to TBD, however the protean presentation makes recognition challenging and the overall incidence is unknown 6 .…”