# A Systematic Review Illustrates the Expanding Clinical and Molecular Landscape of Helsmoortel-Van der Aa Syndrome

## TL;DR

This systematic review expands the understanding of Helsmoortel-Van der Aa syndrome by summarizing clinical and genetic findings from 105 cases, highlighting new features and the need for multidisciplinary care.

## Contribution

The study provides the first comprehensive synthesis of the clinical and molecular spectrum of HVDAS beyond the initial 2019 cohort.

## Key findings

- The review identifies expanded phenotypic features such as visual anomalies, congenital heart defects, and gait disturbances.
- Advances in ADNP methylation profiling improve diagnostic accuracy and variant interpretation.
- Phenotypic heterogeneity is attributed to better clinical recognition and publication bias toward severe cases.

## Abstract

Background: Helsmoortel-Van der Aa syndrome (HVDAS) is a rare multisystemic neurodevelopmental disorder caused by pathogenic variants in the Activity-Dependent Neuroprotective Homeobox Protein (ADNP) gene. Since the extensive clinical description of a cohort of 78 affected individuals in 2019, numerous reports described additional cases affected by the condition. However, no systematic synthesis of the clinical and molecular spectrum of these additional individuals has been conducted to date. Methods: In accordance with the PRISMA 2020 guidelines, we performed a systematic review of all publications describing individuals with genetically confirmed HVDAS. Clinical characteristics, comorbidities, and developmental milestones were systematically extracted to illustrate novel or underrecognized manifestations. Results: A total of 105 individuals reported across 34 publications were included. Of these, 66 were clinically and genetically evaluated, and 39 were analyzed only at the genetic level. Our analysis refines the phenotypic spectrum of HVDAS, including developmental delay, visual anomalies, and congenital heart defects. The additional literature also allows us to characterize in more detail the ophthalmological abnormalities, gait disturbances, and the cognitive profile of HVDAS. Advances in ADNP methylation profiling further enhance diagnostic precision and variant interpretation in this evolving neurodevelopmental syndrome. Conclusions: This systematic review provides a comprehensive synthesis of the clinical, genetic, and epigenetic landscape of HVDAS. It underscores the multisystemic nature of the disorder and the need for multidisciplinary management. The expanding phenotypic heterogeneity likely reflects both improved clinical recognition of the more subtle features and the tendency to prioritize publication of more complex or severely affected cases.