Interpretation of de novo mutations (DNM) and genetic counseling for sporadic hearing loss based on family trio-based sequencing.

Abstract

De novo mutations (DNMs) are significant genetic factors contributing to sporadic hearing loss (HL) and complex HL syndromes. To analyze the genetic counseling characteristics and interpretation of pathogenic DNMs for sporadic HL, we retrospectively analyze the clinical information of probands and their parents from 410 sporadic HL core pedigrees enrolled in the "Chinese Deafness Genome Project (CDGP)" between October 2015 and October 2023. We apply family trio-based genome sequencing (targeted gene capture and high throughput sequencing, mitochondrial genome sequencing, and copy number variants analysis) and validate the samples of their unaffected-parents. Homologous allele sequencing is used to identity by descent (IBD) in the DNM family trios. The results reveal that 7.3% (30 cases) of the probands in these sporadic hearing loss core pedigrees carry 17 types of autosomal dominant gene de novo single nucleotide variants (SNVs), insertions/deletions (Indels), and one type of de novo copy number variation, encompassing all types of DNM. Among them, WFS1 c.2051C>T, ATP1A3 c.2452G>A, and ACTG1 c.94C>T are common DNM in sporadic HL. The genotype C>T transversion exhibit a high number (34.6%). Clinical feature analyses also show that 56.7% (17/30) of the probands have non-syndromic HL, but more than half of them (52.9%, 9/17) carry pathogenic genotypes clearly associated with "syndromic HL", possibly exhibiting temporary "mimic" non-syndromic HL phenotypic characteristics. The average parental ages at childbirth for the 30 probands are 29.4 years for fathers and 28.3 years for mothers, with 13.3% of fathers or mothers aged ≥35 years. Additionally, among the family structure of the proband of genetic counseling, 63.3% are single-child families with a clear desire for another child, and 16.7% of the probands' parents seek prenatal genetic counseling for conceiving a "second child". During genetic counseling, it is essential to test the "family proband-parents' trios" core pedigree as a unit to analyze the genetic contribution of DNMs to HL. Furthermore, there is a certain correlation between the occurrence of DNMs and increasing parental age at childbirth. Therefore, for families with a history of DNM-associated sporadic HL, it is necessary to collect clinical information such as the parental age at childbirth and obstetric history of hearing-healthy parents. For these families planning another child, it is recommended to undergo prenatal diagnosis for the identified DNM pathogenic variations after conception and pay attention to the pregnancy outcome.