Confirmation and expansion of the phenotype of the TCEAL1-related neurodevelopmental disorder.

Researchers studied four people with a rare genetic condition called TCEAL1-related disorder. This condition causes developmental delays (especially with speech), learning difficulties, autism-like behaviors, low muscle tone, and walking problems. The study included two adults, which helped identify new symptoms that appear later in life: increased appetite, weight gain, and hormone problems. This information helps doctors better understand and counsel families affected by this rare condition.

This study reports on four new individuals with TCEAL1-related neurodevelopmental disorder, expanding understanding of this rare genetic condition. The disorder is caused by loss-of-function variants in the TCEAL1 gene and presents with developmental delay (particularly affecting speech), intellectual disability, autistic-like behaviors, hypotonia, and gait abnormalities. The study includes two adults, revealing new features not previously reported: hyperphagia, obesity, and endocrine abnormalities including hyperinsulinemia, hyperandrogenemia, and polycystic ovarian syndrome. Additional features include mild facial dysmorphism and ocular, gastrointestinal, and immunologic abnormalities.

The research used trio exome or genome sequencing for identification and included X chromosome inactivation and RNA-seq studies to understand molecular mechanisms.

Clinicians should monitor for endocrine abnormalities and metabolic complications in adults with TCEAL1-related disorder. Early identification through genetic testing enables appropriate counseling and management. The expanded phenotype description aids in clinical recognition and diagnosis of this rare condition.

Very small sample size of four individuals limits generalizability. Study design not specified. Long-term outcomes data limited to two adult cases. Functional studies provide preliminary molecular insights but may require validation in larger cohorts.

Numerous contiguous gene deletion syndromes causing neurodevelopmental disorders have previously been defined using cytogenetics for which only in the current genomic era the disease-causing genes have become elucidated. One such example is deletion at Xq22.2, previously associated with a neurodevelopmental disorder which has more recently been found to be caused by de novo loss-of-function variants in TCEAL1. So far, a single study reported six unrelated individuals with this monogenetic disorder, presenting with syndromic features including developmental delay especially affecting expressive speech, intellectual disability, autistic-like behaviors, hypotonia, gait abnormalities and mild facial dysmorphism, in addition to ocular, gastrointestinal, and immunologic abnormalities. Here we report on four previously undescribed individuals, including two adults, with de novo truncating variants in TCEAL1, identified through trio exome or genome sequencing, further delineating the phenotype of the TCEAL1-related disorder.

Whereas overall we identify similar features compared to the original report, we also highlight features in our adult individuals including hyperphagia, obesity, and endocrine abnormalities including hyperinsulinemia, hyperandrogenemia, and polycystic ovarian syndrome. X chromosome inactivation and RNA-seq studies further provide functional insights in the molecular mechanisms. Together this report expands the phenotypic and molecular spectrum of the TCEAL1-related disorder which will be useful for counseling of newly identified individuals and their families.