Homozygous loss of ADAMTS19 in human families causes progressive HVD.Ī, Family 1 has a genomic deletion of ADAMTS19 coding exons 1–8. In support of this observation, ADAMTS19 shows a strong signature of negative selection against LOF variants in the Exome Aggregation Consortium and gnomAD databases with a probability of LOF intolerance (pLI score) of 0.95 and an observed/expected score of 0.39, respectively, categorizing it as extremely intolerant to LOF variants 13 ( Supplementary Fig. No homozygous LOF variant carriers were found in public genetic databases such as gnomAD, Geno 2MP (, accessed February 2019) or in any in-house databases (approximately 5,000 exomes of European ancestry for congenital heart disease, approximately 900 exomes of Arabic ancestry) indicating that homozygous LOF for ADAMTS19 is extremely rare 13. In contrast to other ADAMTS-linked diseases, no syndromic features were identified in any of the affected patients, suggesting that LOF of ADAMTS19 leads to isolated, nonsyndromic, progressive HVD in humans 14– 18. Despite the nonsignificant linkage results, ADAMTS19 represents the only gene for which all affected individuals showed homozygous, rare LOF alleles, making it a strong candidate gene for the observed HVD ( Supplementary Table 2). A recessive linkage analysis of the ADAMTS19 locus for both families resulted in a nonsignificant log-of-odds score (log-of-odds = 1.59) due to the limited number of affected individuals. 1e, ,f, f, Supplementary Table 1 and Supplementary Videos 1– 3). Two of their children are homozygous for this mutation and were diagnosed with HVD early on in life that progressively worsened while their heterozygous siblings and parents showed no signs of the disease ( Fig. In family 2, the parents who are second cousins carry a rare truncating, nonsense mutation in ADAMTS19 (rs772148624, NM_133638.5:c.1984C>T, ADAMTS19:p.Arg656*, Genome AggregationDatabase(gnomAD)frequency = 7.959 × 10 −6 Fig. Two of the children in this family are homozygous for the deletion and were diagnosed with HVD disease early on in life ( Supplementary Table 1). 1a) and both carry a rare copy number variant overlapping exons 1–8 of ADAMTS19 (ref. The parents in family 1 (I-1 and I-2) are second cousins ( Fig. Exome sequencing revealed homozygous, rare loss-of-function (LOF) alleles in four affected individuals in the gene ADAMTS19. Here, we identify two unrelated consanguineous families with a recessive inheritance pattern of early-onset HVD without a syndromic phenotype ( Supplementary Note). Despite the high frequency of different types of HVD, such as mitral valve prolapse and bicuspid aortic valve (BAV), only a minority of cases have an underlying monogenic cause in a nonsyndromic context 2– 7. Previous studies have highlighted the complex genetic architecture of heart valve disease (HVD) 11, 12. Valvular heart disease can affect any of the four cardiac valves and is often associated with syndromic disorders 8– 10. Upregulation of endocardial Krüppel-like factor 2 in Adamts19 knockout mice precedes hemodynamic perturbation, showing that a tight balance in the Wnt–Adamts19–Klf2 axis is required for proper valve maturation and maintenance. Expression analysis using a lacZ reporter and single-cell RNA sequencing highlight Adamts19 as a novel marker for valvular interstitial cells inference of gene regulatory networks in valvular interstitial cells positions Adamts19 in a highly discriminatory network driven by the transcription factor lymphoid enhancer-binding factor 1 downstream of the Wnt signaling pathway. Homozygous knockout mice for Adamts19 show aortic valve dysfunction, recapitulating aspects of the human phenotype. Whole-exome sequencing revealed homozygous, truncating nonsense alleles in ADAMTS19 in all four affected individuals. ![]() ![]() Here we identify two consanguineous families, each with two affected family members presenting with progressive heart valve disease early in life. Despite the high frequency of heart valve disease, only a handful of genes have so far been identified as the monogenic causes of disease 2– 7. ![]() Although the initial observation is often localized (for example, to the aortic or mitral valve), disease manifestations are regularly observed in the other valves and patients frequently require surgery. Valvular heart disease is observed in approximately 2% of the general population 1.
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