‘Isolated’ germline mosaicism in the phenotypically normal father of a girl with X-linked hypophosphatemic rickets

Abstract

Objective X-linked hypophosphatemic rickets (XLHR) is the most common form of inherited rickets caused by pathogenic variants of PHEX gene with an X-linked dominant inheritance pattern. Precise molecular diagnosis of pathogenic variant will benefit the genetic counseling and prenatal diagnosis for the family with XLHR. Here, we presented an ‘isolated’ germline mosaicism in the phenotypically normal father of a girl with XLHR. Methods and results For the initial molecular screen of PHEX gene, DNA samples of the proband and her parents were extracted from their peripheral blood samples respectively. Sanger sequencing found a ‘de novo’ novel heterozygous variant, c.1666C>T(p.Q556X), at the PHEX gene in the proband, but not in her phenotypically healthy parents. Due to an occasional abnormality of his serum phosphate previously, further examinations for the father were taken to exclude the possibility of paternal mosaicism. Eight samples from different tissues were analyzed for PHEX gene by Sanger sequencing. Surprisingly, one ‘isolated’ germline mosaicism was detected only in his sperm with an estimated frequency of 26.67%. The mosaic allele was identical to the c.1666C>T(p.Q556X) variant in the proband. Conclusions This is the first case of ‘isolated’ germline mosaicism with pathogenic PHEX variant. Our study provides accurate diagnosis and valuable counseling for this family. This report also alerts clinicians and geneticists to exclude the possibility of the isolated germline mosaicism and prevent intrafamilial recurrences of inherited diseases.

Origin and timing of de novo variants implicated in type 2 von Willebrand disease

“…Importantly, in family 4, linkage analysis revealed that the proband's young brother and sister (Figure 2A) received the same SNV haplotype sequence from their paternal grandfather (dashed rectangle); however, they did not receive the variant and showed normal coagulation tests (data not shown). These results provided strong evidence to support that the father had an isolated germline mosaicism disorder, which has also been noted in other genetic disorders 39,40 . Another interesting finding in family 1 was that although the proband's sister received the same SNV haplotype sequence from the mother (dashed rectangle, Figure 1A), she did not carry the same variant.…”

Should we genotype the sperm of fathers from patients with ‘de novo’ mutations?

“…In this issue of the European Journal of Endocrinology, Lin et al report a de novo heterozygous nonsense variant in the PHEX gene in a X-linked hypophosphatemic rickets patient (1). Lin et al described a germline mosaicism in the sperm of the unaffected father of the proband, providing the opportunity to discuss the concept of isolated germline mosaicism.…”

Living birth following preimplantation genetic testing for monogenic disorders to prevent low-level germline mosaicism related Nicolaides–Baraitser syndrome

“…Gonadal mosaicism has been reported in a variety of dominant (Monies et al, 2019) or X-linked conditions (Zhong et al, 2021) and should be considered in all cases of apparent denovo variation. Sperm mosaic can cause a wide variety of diseases as many types of genetic perturbation can occur in the sperm (Bell et al, 2020;Breuss et al, 2020;Lin et al, 2020;Li et al, 2021). It means that sperm mosaic without a visible phenotype is probably underestimated in cases of DNMs when only one fetus or child is affected.…”

“…Any type of genetic variant can occur in the sperm, including singlenucleotide variations (SNVs), nonrecurrent copy-number variations (CNVs), small insertions and deletions (INDELS), and copy-number-neutral structural variations (Breuss et al, 2021). As the genetic information in the father's sperm can be transmitted to the next generation, sperm mosaicism could potentially be present in any cases reported as de-novo mutations (DNMs) in the child and cause a large proportion of severe sporadic diseases in childhood (Telenius et al, 1995;Zhang et al, 2019;Breuss et al, 2020;Lin et al, 2020). Depending on different properties, the recurrence rate of the DNMs could range from 0.011% to 28.5% (Jonsson et al, 2018).…”