TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities.

White matter hyperintensities (WMHs) of the brain are important markers of aging and small-vessel disease. WMHs are rare in healthy children and, when observed, often occur with comorbid neuroinflammatory or vasculitic processes. Here, we describe a complex 4 kb deletion in 2q36.3 that segregates with early childhood communication disorders and WMH in 15 unrelated families predominantly from Southeast Asia. The premature brain aging phenotype with punctate and multifocal WMHs was observed in ~70% of young carrier parents who underwent brain MRI. The complex deletion removes the penultimate exon 3 of TM4SF20, a gene encoding a transmembrane protein of unknown function. Minigene analysis showed that the resultant net loss of an exon introduces a premature stop codon, which, in turn, leads to the generation of a stable protein that fails to target to the plasma membrane and accumulates in the cytoplasm. Finally, we report this deletion to be enriched in individuals of Vietnamese Kinh descent, with an allele frequency of about 1%, embedded in an ancestral haplotype. Our data point to a constellation of early language delay and WMH phenotypes, driven by a likely toxic mechanism of TM4SF20 truncation, and highlight the importance of understanding and managing population-specific low-frequency pathogenic alleles.

Defining Developmental-Behavioral Pediatrics.

There is an insufficient number of specialty developmental-behavioral pediatrics (DBP) physicians, despite nearly 25% of children and adolescents having a developmental, learning, behavioral, or emotional problem. In the nearly 20 years since becoming a board-certified subspecialty, the definition of DBP clinical practice remains somewhat unclear. This lack of clarity likely contributes to recruitment challenges and workforce issues, and limited visibility of DBP among parents, other professionals, payors, and administrators. Defining DBP is therefore an important step in the survival and growth of the field. In this paper, we describe the methodology used to develop this definition along with the origins of DBP, the persistent challenges to defining its scope, what training in DBP involves, and what distinguishes DBP from other overlapping fields of medicine. We propose the following definition of DBP: developmental-behavioral pediatrics (DBP) is a board-certified, medical subspecialty that cares for children with complex and severe DBP problems by recognizing the multifaceted influences on the development and behavior of children and addressing them through systems-based practice and a neurodevelopmental, strength-based approach that optimizes functioning. Developmental behavioral pediatricians care for children from birth through young adulthood along a continuum including those suspected of, at risk for, or known to have developmental and behavioral disorders.