A founder variant in the South Asian population leads to a high prevalence ofFANCLFanconi anemia cases in India

Abstract

Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure, predisposition to cancer, and congenital abnormalities. FA is caused by pathogenic variants in any of 22 genes involved in the DNA repair pathway responsible for removing interstrand crosslinks. FANCL, an E3 ubiquitin ligase, is an integral component of the pathway, but patients affected by disease‐causing FANCL variants are rare, with only nine cases reported worldwide. We report here a FANCL founder variant, anticipated to be synonymous, c.1092G>A;p.K364=, but demonstrated to induce aberrant splicing, c.1021_1092del;p.W341_K364del, that accounts for the onset of FA in 13 cases from South Asia, 12 from India and one from Pakistan. We comprehensively illustrate the pathogenic nature of the variant, provide evidence for a founder effect, and propose including this variant in genetic screening of suspected FA patients in India and Pakistan, as well as those with ancestry from these regions of South Asia.

Five Novel Deleterious Variants in FANCA, FANCF and FANCG Identified in Pakistani Fanconi Anemia Families Using Exome Sequencing

“…However, the presence of homozygous pathogenic variants in our data is consistent with prior studies reporting an approximately 70% rate of consanguineous marriages in Pakistan (66)(67)(68). Nine of the 14 pathogenic variants identi ed have been previously reported (Table 2) (12,(14)(15)(16)(17)(18).…”

“…Only two families had compound heterozygous inheritance (both in FANCA). Two families were homozygous for the FANCL founder variant (18). We were unable to evaluate consanguinity in 14 of the families in this study due to lack of parental DNA samples.…”

“…Unrelated probands 6-FA and 7-FA were both homozygous for a recently identi ed FANCL South Asian founder variant. Donovan et al established this single nucleotide variation (NC_000002.11:g.58387243C > T) induces aberrant mRNA splicing to skip exon 13 (c.1021_1092del, p.Trp341_Lys364del, rs577063114), resulting in a 24 amino acid deletion from the RING domain of FANCL (18). The genomAD MAF of this variant is 0.001994% in all populations and 0.01634% in South Asian populations.…”

“…The only large deletions reported were in FANCA, similar to our ndings and consistent with others. We also identi ed the recently identi ed FANCL founder mutation (c.1092G > A, p.Trp341_Lys364del) in 2 families from Pakistan (18). that in the absence of overt dysmorphology, the diagnosis of FA may be delayed or missed because chronic malnutrition and its complications may confound rare disease diagnoses (66).…”

Should FANCL heterozygous pathogenic variants be considered as potentially causative of primary ovarian insufficiency?

“…In FA, FANCL is the least commonly mutated gene and represents 0.2% of all FA reported to date (Neveling, Endt, Hoehn, & Schindler, 2009). FANCL is responsible for extremely severe forms of FA, with 21 patients reported to date, and no adult form described (Donovan et al, 2020). In all the cases related to biallelic FANCL pathogenic variants (including most often truncating or nonsense variants), no infertility has been reported in the heterozygous parents or the obligate carriers.…”