Supplementary Material for: Clinical and Molecular Characterization of Fanconi Anemia Patients in Turkey

Fanconi anemia (FA) is a rare multigenic chromosomal instability syndrome that predisposes patients to life-threatening bone marrow failure, congenital malformations, and cancer. Functional loss of interstrand cross-link (ICL) DNA repair system is held responsible, though the mechanism is not yet fully understood. The clinical and molecular findings of 20 distinct FA cases, ages ranging from perinatal stage to 32 years, are presented here. Pathogenic variants in <i>FANCA</i> were found responsible in 75%, <i>FANCC</i>, <i>FANCE</i>, <i>FANCJ</i>/<i>BRIP1</i>, <i>FANCL</i> in 5%, and <i>FANCD1</i>/<i>BRCA2</i> and <i>FANCN</i>/<i>PALB2</i> in 2.5% of the subjects. Altogether, 25 different variants in 7 different FA genes, including 10 novel mutations in <i>FANCA</i>, <i>FANCN</i>/<i>PALB2</i>, <i>FANCE,</i> and <i>FANCJ</i>/<i>BRIP1,</i> were disclosed. Two compound heterozygous germline cases were mosaic for one allele, revealing that the incidence of reverse mutations may not be uncommon in FA. Another case with de novo <i>FANCD1/BRCA2</i> and paternally inherited <i>FANCN/PALB2</i> pathogenic alleles at first glance suggested a digenic inheritance, because the presence of a second pathogenic variant in the unexamined regions of <i>FANCD1/BRCA2</i> and <i>FANCN/PALB2</i> were exluded by sequencing and deletion/duplication analysis. A better understanding of the complexity of the FA genotype may provide further access to undiscovered ICL components and apparently dispensable cellular pathways where FA proteins may play important roles.

范科尼贫血（Fanconi anemia, FA）是一种罕见的多基因性染色体不稳定综合征，患者易罹患危及生命的骨髓衰竭、先天性畸形及癌症。目前认为该病的病因是链间交联（interstrand cross-link, ICL）DNA修复系统功能缺失，但具体机制尚未完全阐明。本文报道了20例不同FA病例的临床及分子学特征，患者年龄范围从围产期至32岁。研究发现，75%的病例存在FANCA致病性变异，5%的病例分别涉及FANCC、FANCE、FANCJ/BRIP1、FANCL，另有2.5%的病例携带FANCD1/BRCA2及FANCN/PALB2致病性变异。本研究共在7个不同的FA相关基因中发现了25种不同的变异，其中包括FANCA、FANCN/PALB2、FANCE及FANCJ/BRIP1中的10种新型突变。2例复合杂合生殖系病例存在一个等位基因的嵌合现象，提示反向突变在FA中的发生率或许并不罕见。另有1例病例同时携带新生的FANCD1/BRCA2致病性等位基因，以及父系遗传的FANCN/PALB2致病性等位基因，最初看似符合双基因遗传模式，但后续通过测序及缺失/重复分析排除了FANCD1/BRCA2与FANCN/PALB2未检测区域存在第二种致病性变异的可能。对FA基因型复杂性的进一步深入理解，或有助于发现未被鉴定的ICL修复组件，以及FA蛋白可能发挥重要作用的、看似非必需的细胞通路。