Clinical and genetic characteristics of Chinese patients with congenital cranial dysinnervation disorders

Hongyan Jia; Qian Ma; Yi Liang; Dan Wang; Qinglin Chang; Bo Zhao; Zongrui Zhang; Jing Liang; Jing Song; Yidi Wang; Ranran Zhang; Zhanhan Tu; Yonghong Jiao

doi:10.1186/s13023-022-02582-5

Clinical and genetic characteristics of Chinese patients with congenital cranial dysinnervation disorders

Orphanet J Rare Dis. 2022 Dec 9;17(1):431. doi: 10.1186/s13023-022-02582-5.

Authors

Hongyan Jia^#^{1

2}, Qian Ma^#^{1

2}, Yi Liang^{1

2}, Dan Wang^{1

2}, Qinglin Chang³, Bo Zhao³, Zongrui Zhang³, Jing Liang^{1

2}, Jing Song^{1

2}, Yidi Wang^{1

2}, Ranran Zhang^{1

2}, Zhanhan Tu⁴, Yonghong Jiao^{5

6}

Affiliations

¹ Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
² Beijing Ophthalmology and Visual Science Key Lab, Beijing, 100730, China.
³ Department of Radiology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
⁴ Department of Neuroscience, Psychology and Behaviour, Ulverscroft Eye Unit, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
⁵ Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China. yhjiao2001@aliyun.com.
⁶ Beijing Ophthalmology and Visual Science Key Lab, Beijing, 100730, China. yhjiao2001@aliyun.com.

^# Contributed equally.

Abstract

Background: Congenital cranial dysinnervation disorders (CCDDs) are a group of diseases with high clinical and genetic heterogeneity. Clinical examinations combined with Magnetic resonance imaging (MRI) and whole exome sequencing (WES) were performed to reveal the phenotypic and genotypic characteristics in a cohort of Chinese CCDDs patients.

Results: A total of 122 CCDDs patients from 96 families were enrolled. All patients showed restrictive eye movements, and 46 patients from 46 families (47.9%, 46/96) were accompanied by multiple congenital malformations. Multi-positional high-resolution MRI was performed in 94 patients from 88 families, of which, all patients had hypoplasia of the cranial nerves except HGPPS patients and 15 patients from 15 families (17.0%,15/88) were accompanied by other craniocerebral malformations. WES was performed in 122 CCDDs patients. Ten pathogenic variants were detected in KIF21A, TUBB3, and CHN1 genes in 43 families. Three variants were unreported, including KIF21A (c.1064T > C, p.F355S), TUBB3 (c.232T > A, p.S78T) and CHN1 (c.650A > G, p.H217R). Of the 43 probands harboring pathogenic variants, 42 were diagnosed with Congenital Fibrosis of Extraocular Muscles (CFEOM) and one was Duane Retraction Syndrome (DRS). No definite pathogenic variants in known candidate genes of CCDDs were found in sporadic DRS, Möbius Syndrome (MBS) and Horizontal Gaze Palsy with Progressive Scoliosis (HGPPS) patients. The CFEOM patients harboring R380C, E410K and R262H variants in TUBB3 gene and F355S variant in KIF21A gene exhibited syndromic phenotypes.

Conclusions: This study broadened the phenotypic and genotypic spectrums of CCDDs, and it was the largest clinical and genetic investigation for CCDDs patients from China. KIF21A and TUBB3 were the common pathogenic genes in Chinese CFEOM. MRI coupled with WES can provide a supportive diagnosis in patients with clinically suspected CCDDs.

Keywords: Congenital cranial dysinnervation disorders; Genetics; Magnetic resonance imaging; Phenotypic and genotypic characteristics; Whole exome sequencing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Congenital Cranial Dysinnervation Disorders*
Duane Retraction Syndrome* / diagnosis
Duane Retraction Syndrome* / genetics
East Asian People
Fibrosis
Humans
Mobius Syndrome* / diagnosis
Ophthalmoplegia*