Von Hippel-Lindau “Black Forest” mutation inherited in a large Chinese family

Abstract

Background: The Von Hippel-Lindau (VHL) p.Tyr98His (Y98H) mutation is designated as the "Black Forest" founder mutation and has been previously reported in Western countries. This study reports the first recorded Chinese VHL family with the "Black Forest" mutation in Asia.Methods: Paired whole-exome sequencing (WES), Sanger sequencing and immunohistochemistry (IHC) were performed on samples from a large Chinese family to confirm the causative mutation and mutation carriers in the family. Clinical manifestations of the family were summarized and compared with those reported from other patients with the VHL Y98H mutation.Results: The Chinese pheochromocytoma (PCC) family was identified as a VHL type 2 family with a Y98H mutation. There were 4 VHL patients and 11 currently healthy individuals with the mutation. Copy number analysis and SDHB IHC were performed to exclude interference from other pathogenic genes of PCC or paraganglioma (PGL). Conclusions:We report the first recorded instance of a Chinese VHL type 2 family with the "Black Forest" mutation by using WES and Sanger sequencing, which widens the currently recorded presence of the "Black Forest" mutation to China and potentially elsewhere in Asia and indicates that the "Black Forest" mutation does not uniquely evolve in occidental countries. A personalized surveillance approach, which may be more appropriate for affected families, has been recommended to improve quality of life.

Pheochromocytomas and paragangliomas in von Hippel–Lindau disease: not a needle in a haystack

“…A total of 52 studies, assessing 840 participants with vHL type 2, provided information on the frequency of PPGL. Most of these studies were conducted in Europe ( n =18) ( 16 , 17 , 21 , 25 , 26 , 28 , 29 , 62 , 66 , 68 , 70 , 71 , 72 , 73 , 76 , 83 , 91 , 92 ), followed by Eastern Asia ( n =17) ( 35 , 36 , 40 , 44 , 45 , 47 , 48 , 74 , 75 , 77 , 78 , 79 , 80 , 81 , 82 , 86 , 87 ) and North America ( n =9) ( 53 , 59 , 60 , 61 , 63 , 64 , 65 , 69 , 84 ). All studies assessed patients of all age groups, with the mean onset age of PPGL being 28.8 years (as reported in 21 studies ( 21 , 26 , 35 , 40 , 44 , 47 , 55 , 59 , 60 , 61 , 65 , 67 , 71 , 72 , 74 , 77 , 79 , 85 , 86 , …”

“…All studies assessed patients of all age groups, with the mean onset age of PPGL being 28.8 years (as reported in 21 studies ( 21 , 26 , 35 , 40 , 44 , 47 , 55 , 59 , 60 , 61 , 65 , 67 , 71 , 72 , 74 , 77 , 79 , 85 , 86 , 87 , 88 )). Six studies reported a consecutive sample ( 16 , 17 , 29 , 66 , 77 , 78 ), whereas in 39 studies a convenience sample was assessed ( 21 , 25 , 35 , 45 , 47 , 53 , 56 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 ).…”

“…The frequency of PPGL among participants with vHL type 2 was 60.0% (95% CI = 53.4–66.3%), with moderate heterogeneity being observed ( I 2 = 54.6%) ( 16 , 17 , 21 , 25 , 26 , 28 , 29 , 35 , 36 , 40 , 44 , 45 , 47 , 48 , 53 , 55 , 56 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 ) ( Table 1 ). We observed lower heterogeneity in subgroup analyses restricted to convenience sampling ( I 2 = 25.6%) and to patients whose diagnosis was performed only clinically ( I 2 = 23.1%) (Supplementary Table 7).…”

“…Twenty-eight studies, with a total of 411 participants with vHL type 2A, reported the frequency of PPGL among these patients ( 16 , 25 , 26 , 28 , 29 , 35 , 36 , 47 , 55 , 60 , 61 , 62 , 63 , 65 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 78 , 79 , 80 , 81 , 82 , 85 , 92 ). The pooled frequency of PPGL among participants with vHL type 2A was 58.2% (95% CI = 49.7–66.3%, I 2 = 36.2%) ( Table 1 ) ( 16 , 25 , 26 , 28 , 29 , 35 , 36 , 47 , 55 , 60 , 61 , 62 , 63 , 65 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 78 , 79 , 80 , 81 , 82 , 85 , 92 ). In most subgroup analysis, moderate heterogeneity was observed ( Table 3 ).…”

“…In addition, 58.3%(20,25,26,32,35,37,41,(43)(44)(45)47,52,53,56,58).A total of 52 studies, assessing 840 participants with vHL type 2, provided information on the frequency of PPGL. Most of these studies were conducted in Europe (n=18)(16,17,21,25,26,28,29,62,66,68,(70)(71)(72)(73)76,83,91,92), followed by Eastern Asia (n=17)(35,36,40,44,45,47,48,74,75,(77)(78)(79)(80)(81)(82)86,87) and North Americ...…”