Prevalence and clinical/molecular characteristics of PTEN mutations in Turkish children with autism spectrum disorders and macrocephaly

Abstract

Background Phosphatase and tensin homolog (PTEN) germline mutations are associated with cancer syndromes (PTEN hamartoma tumor syndrome; PHTS) and in pediatric patients with autism spectrum disorder (ASD) and macrocephaly. The exact prevalence of PTEN mutations in patients with ASD and macrocephaly is uncertain; with prevalence rates ranging from 1% to 17%. Most studies are retrospective and contain more adult than pediatric patients, there is a need for more prospective pediatric studies. Methods We recruited 131 patients (108 males, 23 females) with ASD and macrocephaly between the ages of 3 and 18 from five child and adolescent psychiatry clinics in Turkey from July 2018 to December 2019. We defined macrocephaly as occipito‐frontal HC size at or greater than 2 standard deviations (SD) above the mean for age and sex on standard growth charts. PTEN gene sequence analysis was performed using a MiSeq next generation sequencing (NGS) platform, (Illumina). Conclusion PTEN gene sequence analyses identified three pathogenic/likely pathogenic mutations [NM_000314.6; p.(Pro204Leu), (p.Arg233*) and novel (p.Tyr176Cys*8)] and two variants of uncertain significance (VUS) [NM_000314.6; p.(Ala79Thr) and c.*10del]. We also report that patient with (p.Tyr176Cys*8) mutation has Grade 1 hepatosteatosis, a phenotype not previously described. This is the first PTEN prevalence study of patients with ASD and macrocephaly in Turkey and South Eastern Europe region with a largest homogenous cohort. The prevalence of PTEN mutations was found 3.8% (VUS included) or 2.29% (VUS omitted). We recommend testing for PTEN mutations in all patients with ASD and macrocephaly.

Benign goiters requiring thyroidectomy as the signal for PTEN hamartoma tumor syndrome diagnosis

“…Therefore, initiating genetic evaluation and molecular genetic testing for PHTS for all children with autism diagnosis alone may not be practical. Previous reports indicated 2%–27% of children with autism and coexisting large head size (macrocephaly as determined by head circumference of greater than 2 or 4 SD above the mean, measured by occipital frontal circumference) were found to carry PTEN mutations (Drissen et al, 2021; Hobert et al, 2014; Kaymakcalan et al, 2021). The combination of these two signs may also serve as a harbinger for PHTS.…”

Genetic investigations pathway for people with intellectual disability, autism and/or epilepsy

“…This highlights the importance of gathering information on early developmental milestones. Specific clinical features may suggest a specific genetic condition, for example macrocephaly and PTEN gene variation (Kaymakcalan 2021). A deviation in head circumference of more than 1 s.d.…”

Exploring the neurological features of individuals with germline PTEN variants: A multicenter study

“…Among young individuals with PHTS, a macrocephaly/autism syndrome (OMIM 605309) was identified, and PHTS is recognized as among the most common genetic causes of autism spectrum disorder (ASD) 2,4 . Nearly 22% of patients with PHTS have ASD, and 4–17% of individuals with ASD and macrocephaly are suspected to harbor a germline PTEN pathogenic variant 4–7 . Despite the recognition of this neurodevelopmental phenotype in patients with PHTS, little is known about the neurological signs and symptoms experienced by these patients and how these change over time and during critical phases of neurodevelopment.…”

“… 2 , 4 Nearly 22% of patients with PHTS have ASD, and 4–17% of individuals with ASD and macrocephaly are suspected to harbor a germline PTEN pathogenic variant. 4 , 5 , 6 , 7 Despite the recognition of this neurodevelopmental phenotype in patients with PHTS, little is known about the neurological signs and symptoms experienced by these patients and how these change over time and during critical phases of neurodevelopment.…”