# Genotype–phenotype correlations in 9q34.3 microdeletion syndrome: a study of 35 Mainland Chinese patients

## TL;DR

This study examines 35 Chinese patients with KLEFS1 to understand how genetic changes in EHMT1 relate to physical and developmental traits.

## Contribution

The study identifies 17 novel EHMT1 variants and reports on prenatal and facial features in a previously underrepresented population.

## Key findings

- 17 novel variants of EHMT1 were identified, expanding the genetic understanding of KLEFS1.
- Patients with larger deletions showed significantly higher frequencies of specific physical traits like everted lower lip and renal anomalies.
- EHMT1 haploinsufficiency was found to contribute to most key phenotypes of KLEFS1.

## Abstract

To provide the molecular characterizations and clinical profiles in patients with KLEFS1(Kleefstra syndrome 1) of Chinese ethic group and explore the genotype-phenotype correlation in this underrepresented population.

A total of 35 Mainland Chinese patients with KLEFS1 were reported in the present study. The clinical data were assessed through reviewing medical records and standardized medical history questionnaires. We analyzed EHMT1 variants and 9q34.3 microdeletion and performed genotype–phenotype correlation in two groups.

17 novel variants of EHMT1 were identified, adding to the genetic landscape of the disorder. For the first time, we retrospectively describe the prenatal presentations and assess facial dysmorphisms in our cohort. There was no significant difference between the two groups in prevalence of clinical manifestations such as DD/ID, neurological symptoms, behavioral issues, obesity, congenital cardiac anomalies, male genital anomalies, or most other related clinical features, including developmental quotients (DQ). However, the frequencies of everted lower lip, small and spaced teeth, short neck, and renal anomalies were significantly higher among patients with deletions encompassing more than EHMT1 compared to those with EHMT1 variants (or deletions only disrupting EHMT1), with rates of 20% vs. 83.3% (P = 0.014), 14.3% vs. 80%(P = 0.017)13.3% vs. 66.7% (P = 0.031) and 5.3% vs. 42.9% (P = 0.047) respectively.

This is the largest series of patients with KLEFS1 published to date in Mainland China. EHMT1 haploinsufficiency contributes to the majority of important phenotypes of KLEFS1. Our findings enrich our knowledge of 9q34.3 microdeletion and enhance our comprehension of the pathogenic molecular mechanisms of EHMT1.

The online version contains supplementary material available at 10.1186/s13023-025-04076-6.