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Chu et al. Rare Dis Orphan Drugs J 2023;2:2 https://dx.doi.org/10.20517/rdodj.2022.25 Page 7 of 10

adult/later complications is limited. The detection of this variant has also been observed in other geographic
regions/ethnicities, as it has been reported in three Caucasian patients, one Indian patient, one patient from
Germany, and two patients from Oman [13-15,17] .

Despite the prevalence and identification of the c.811C>T variant in multiple individuals with KS, this
variant has never been observed in East Asians, in both the disease cohort and the unaffected population.
This variant is found to be absent from East Asian populations in gnomAD version 2.1.1 and 3.1.2 with
population sizes of 9,977 and 2,604, respectively; while 17 heterozygous alleles are observed in other
populations (11 in non-Finnish European, four in African/African American, and two in South Asian). As it
is uncommon to observe two patients with such a rare disease harbouring the same variant in a small
geographical region of Hong Kong (with an estimated population of around 7.51 million in 2019), while a
carrier of the variant has never been seen in a large population database, we have further investigated the
allelic frequency in local cohorts. By reviewing data from 1,700 individuals from three local cohorts (in-
house WGS data from the Hong Kong Genome Project, in-house WES data from the University of Hong
Kong, and an open variant database of WES data) , the allelic frequency of c.811C>T remained as zero. It
[18]
is possible that these two patients may have been linked by a common ancestor who carried the variant
multiple generations ago. Additionally, this variant is also observed in multiple populations of different
ancestry; it is also possible that this site has a higher chance of mutation occurrence.

By reviewing the reported KS patients in medical literature, we describe the mutation spectrum of KS in
East Asians. A total of 15 variants were identified in the FERMT1 gene in Chinese and Japanese populations
[Figure 2]. Similar findings of loss-of-function variants being the predominant mutation type spanning
across the FERMT1 gene have been observed, and consanguinity contributed to the identification of
homozygous variants in multiple reports. The majority of the reported mutations in FERMT1 affected
splicing, followed by frameshift variants, nonsense variants, large exonic deletions, and missense variants. A
recurring homozygous splice site deletion of c.1089+1del was reported in four Japanese patients, with the
exon-8-skipped in-frame transcript as the major product, resulting in a functionally defective truncated
kindlin-1 protein [17,19,20] . The same variant was also reported in compound heterozygous with another
[19]
nonsense variant c.1761T>A in another Japanese patient . Two other splice variants (c.1139+1G>A and
c.1861-1G>A) have been reported in homozygous state in two Chinese patients [21,22] . Homozygous frameshift
mutations, including c.220delC in exon 3, c.994_995delCA in exon 8, and c.1885_1901del in exon 15, were
reported in three Chinese patients, all of which were predicted to cause a premature stop codon [23-25] . Ohashi
et al. observed homozygous nonsense variant c.1761T>A in a Japanese patient and Li et al. reported two
compound heterozygous nonsense mutations (c.193C>T, c.277C>T) in a Chinese patient [23,26] . Large deletion
caused by Matrix Attachment Region elements mediated homologous recombination or Alu-mediated
homologous recombination has been reported in two Chinese patients born to consanguineous parents, one
of which is a 3017-bp deletion mutation spanning exons 7-9 (g.63601_66617del) and the other one is a 17-
kb homozygous deletion spanning the introns 1-6, both are presumed to cause nonsense-mediated mRNA
decay [27,28] . Apart from null variants, a missense homozygous variant c.1343T>A of uncertain significance
has been reported in a Chinese patient with a clinical presentation of atrophic erythema and
telangiectasia .
[29]
We also expanded the investigation of the mutation spectrum of FERMT1 to patients of non-Chinese
descent. A recent study by Li et al published in 2021 summarized 91 different pathogenic FERMT1
[23]
mutations in patients with Kindler syndrome . After further review of Clinvar and LOVD databases, 27
additional pathogenic/likely pathogenic variants were identified in the FERMT1 gene, summing up to 118
variants. These 118 variants are scattered throughout the entire FERMT1 gene without obvious mutational