A compound heterozygosity of two haplotypes in the TTN gene contributes to risk for Cleft Lip and Palate in a recessive manner

Cleft lip and palate (CLP) are complex congenital anomalies with multifactorial etiology and significant genetic heterogeneity. This study aimed to elucidate the genetic basis of nonsyndromic CLP in an Indian family, wherein phenotypically normal parents had three affected offspring, including monozygotic twins, all presenting with bilateral complete CLP. Whole exome sequencing (WES) identified a compound heterozygous haplotype in the TTN gene shared by all affected siblings. The paternal haplotype comprised variants c.96140C>T (p.Thr32047Met), c.77412C>G (p.Phe25804Leu), c.2605A>T (p.Thr869Ser), and c.18663A>C (p.Glu6221Asp), while the maternal haplotype included variants c.107779G>A (p.Glu35927Lys), c.103147G>C (p.Glu34383Gln), c.63907G>A (p.Val21303Met), and c.26863A>G (p.Ile8955Val). In silico analyses predicted these variants to have deleterious effects on protein structure and function, consistent with a recessive mode of inheritance. Although TTN is primarily known for its role in muscle structure and function, emerging evidence implicates its involvement in craniofacial development. This study expands the phenotypic spectrum of TTN-associated disorders and suggests a novel role for TTN in nonsyndromic CLP. These findings underscore the importance of comprehensive genomic analyses in unraveling the molecular mechanisms underlying complex congenital anomalies.