Prenatal-Onset Recessive Titinopathies: Clinical Spectrum, Genotype-Phenotype Correlations, and Outcomes.

Background/Objectives: Recessive titinopathies caused by biallelic TTN truncating variants (TTNtvs) present a clinically heterogeneous spectrum from fetal demise to late-onset slowly progressive distal muscular dystrophy. Prognostic counseling is challenging due to the vast size of the TTN gene, complex splicing patterns, and differential expression throughout developmental stages and tissues. This paper aims to delineate the regional genotype patterns and clinical characteristics of recessive titinopathies described from the prenatal period onwards to inform genotype-phenotype associations and genetic counseling. Methods: We analyzed clinical and genetic data from a prenatal-onset cohort with biallelic TTNtvs from both previously reported cases and novel cases from our center. To characterize the regional distribution of biallelic variants within this specific cohort, a two-dimensional scatter plot was utilized to map variants onto 10 biological regions (R1-R10) and 55 analytical units (U1-U55). We also performed Fisher's exact tests on the subset of 50 cases with confirmed survival records to evaluate statistically significant associations between biallelic regional or percent spliced-in (PSI) thresholds combinations and severe clinical endpoints (intrauterine demise or death before 5 years). Results: A total of 96 prenatal cases from 76 unrelated families were analyzed. Decreased fetal movement was the most commonly reported symptom, observed in 81.3% (78/96) of cases, which was followed by arthrogryposis in 45.8% (44/96) and amniotic fluid volume abnormalities in 35.4% (34/96). Additionally, of the 95 cases with known pregnancy outcomes, 25.3% (24/95) resulted in termination and 11.6% (11/95) resulted in intrauterine demise (IUD), while 63.2% (60/95) reached birth with over 16.7% (10/60) being preterm. Among 60 live-born infants, severe postnatal morbidity was high: 45.0% (27/60) experienced respiratory failure, and 33.3% (20/60) died before the age of five. In this cohort, 84.4% (81/96) of cases possessed at least one TTNtv in either the metatranscript-only or A-band regions. The most common biallelic changes involved TTNtvs in both the A-band and metatranscript-only regions, accounting for 35.4% (34/96) of cases, followed by metatranscript-only combined with I-band variants at 16.7% (16/96), regardless of the PSI score of exons. Overall, 83.3% (80/96) had ≥1 variant on low-PSI (<50%) exons, and 19.8% (19/96) had both alleles on these low-PSI exons. In the 50 patients with confirmed survival records, biallelic changes (excluding splice-site variants) affecting both high-PSI (>90%) exons were significantly associated with severe outcomes (intrauterine demise or death before 5 years; exact p = 0.015), whereas the metatranscript-only plus I-band combination conferred a significantly lower risk of lethality before 5 years of age (exact p = 0.001). Conclusions: Our findings add to the accumulating evidence that TTNtvs on low PSl exons or metatranscript-only regions are frequently observed among reported prenatal-onset recessive titinopathy. Health surveillance for heterozygous carriers among family members is warranted due to the substantial risk for adult-onset dilated cardiomyopathy and peripartum cardiomyopathy.