Novel Compound Heterozygous Mutations in TTI2 Cause Syndromic Intellectual Disability in a Chinese Family

Abstract

Telomere maintenance 2 (TELO2)–interacting protein 2 (TTI2) interacts with TTI1 and TELO2 to form the Triple T complex, which is required for various cellular processes, including the double-strand DNA break response, nonsense-mediated mRNA decay, and telomerase assembly. Herein, we identified compound heterozygous mutations in TTI2 using whole-exome sequencing (WES) in a Chinese family with a recessive inheritance pattern of syndromic intellectual disability. The patients displayed intellectual disability, aggressive and self-injurious behaviors, facial dysmorphic features, microcephaly, and skeletal anomalies. In addition, one patient showed cerebral white matter abnormality. Maternal novel indel mutation resulted in a premature termination codon and nonsense-mediated mRNA decay. Paternal reported c.1100C > T mutation changed the highly conserved proline to leucine that located in the DUF2454 domain. Immunoblotting experiments showed significantly decreased TTI2, TTI1, and TELO2 in the patients’ lymphocytes. These results indicated that TTI2 loss-of-function mutations might cause an autosomal-recessive syndromic intellectual disability by affecting the Triple T complex. Our report expands the genetic causes of syndromic intellectual disability in the Chinese population.

Novel Homozygous TTI2 Variant Causing Autosomal Recessive Syndromic Intellectual Disability and Primary Microcephaly from Pakistan: A Case Report (Exome Report)

“…e variant is not reported in population database (gnomAD) and applicable computational tools such as MutationTaster predict this insertion to be deleterious, and the reported phenotype in our patient is consistent with previous reports [7,8]. A loss-of-function variant has been reported to be disease causing [9]. erefore, we propose a reclassification of this variant as pathogenic according to ACMG criteria [10] (ACMG criteria scores PVS1, PM2, PM4, and PP4).…”

“…In 2020, a single French Canadian case born from second cousin heterozygous parents was reported with homozygous TTI2 variant c.950A > T (p.Asp317Val) presenting with microcephaly and short stature but no intellectual disability [19]. Earlier in 2019, two groups of compound heterozygous TTI2 variants were described with intellectual disability and microcephaly; however, none of the reported individuals were homozygous for this variant [9,20]. Previously another TTI2 variant c.1307T > A(p.Ile436Asn) was described among three siblings born from consanguineous parents; contrary to our case, all the siblings had normal neonatal period and presented with progressive microcephaly at adult age and cognitive impairment [5].…”

System genetics in the rat HXB/BXH family identifies Tti2 as a pleiotropic quantitative trait gene for adult hippocampal neurogenesis and serum glucose

“…dysmorphic facial features, short stature, speech and movement disorders, and skeletal deformations[72,[84][85][86]. Similar abnormalities were observed in children carrying TELO2 mutations[87,88].…”

Whole-exome sequencing identifies homozygous mutation in TTI2 in a child with primary microcephaly: a case report

“…We described the first homozygous c.950A > T (p.Asp317Val) mutation in TTI2 gene causing primary progressive microcephaly and short stature. During the preparation of this manuscript, two other groups report compounds heterozygous mutations in children with intellectual disabilities and microcephaly (Table 1), but none were homozygous for this mutation [8,9].. Another mutation, c.1307 T > A (p.Ile436Asn), in TTI2 gene was previously described in three siblings born from healthy first cousin parents [6]. Contrary to our case, the siblings had normal neonatal period and developed progressive microcephaly with OCF reaching − 3/− 4 SD at 30-36 years old.…”

“…A mutation in TTI2 was previously descr ibed in mental retardation, autosomal recessive 39 in three affected siblings with microcephaly at 30-36 years of age [6].. Recently, two publications reported cases of compound heterozygous mutations, implying that the clinical spectrum of TTI2 is evolving [8,9]. This disorder is characterized by reduced intellectual functioning associated with impairment in adaptative behavior, delayed psychomotor development and short stature.…”