Extended Phenotyping and Functional Validation Facilitate Diagnosis of a Complex Patient Harboring Genetic Variants in MCCC1 and GNB5 Causing Overlapping Phenotypes

Zhuo Shao,Asim Ali,Ikuo Masuho,Andreas Schulze,Erika Tavares,Jason T Maynes,Peter Kannu,Kirill A Martemyanov,Ajoy Vincent,Anupreet Tumber,Stacy Hewson

doi:10.3390/genes12091352

Abstract

Identifying multiple ultra-rare genetic syndromes with overlapping phenotypes is a diagnostic conundrum in clinical genetics. This study investigated the pathogenicity of a homozygous missense variant in GNB5 (GNB5L; NM_016194.4: c.920T > G (p. Leu307Arg); GNB5S; NM_006578.4: c.794T > G (p. Leu265Arg)) identified through exome sequencing in a female child who also had 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency (newborn screening positive) and hemoglobin E trait. The proband presented with early-onset intellectual disability, the severity of which was more in keeping with GNB5-related disorder than 3-MCC deficiency. She later developed bradycardia and cardiac arrest, and upon re-phenotyping showed cone photo-transduction recovery deficit, all known only to GNB5-related disorders. Patient-derived fibroblast assays showed preserved GNB5S expression, but bioluminescence resonance energy transfer assay showed abolished function of the variant reconstituted Gβ5S containing RGS complexes for deactivation of D2 dopamine receptor activity, confirming variant pathogenicity. This study highlights the need for precise phenotyping and functional assays to facilitate variant classification and clinical diagnosis in patients with complex medical conditions.

Highlights

Whole exome sequencing (WES) is increasingly used for the diagnosis of patients with suspected Mendelian genetic disorders [1]
Biallelic pathogenic variants in the G protein subunit beta 5 (GNB5) gene are associated with a broad range of clinical presentations, with fewer than 30 patients reported in the literature [5,6,7,8,9,10,11]
The female proband born to consanguineous parents of Cambodian descent (Figure 1A) has been followed in the inherited metabolic disease clinic since birth due to 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency identified on newborn screening

Summary

Introduction

Whole exome sequencing (WES) is increasingly used for the diagnosis of patients with suspected Mendelian genetic disorders [1]. Biallelic pathogenic variants in the G protein subunit beta 5 (GNB5) gene are associated with a broad range of clinical presentations, with fewer than 30 patients reported in the literature [5,6,7,8,9,10,11]. Homozygous or compound heterozygous variants with at least one null allele in GNB5 cause intellectual developmental disorder with cardiac arrhythmia (IDDCA; MIM: 617173) associated with severe intellectual disability (ID) [12]. Biallelic missense variants in GNB5 cause language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmia (LADCI; MIM: 617182), ref [12,13] associated with mild or no ID. A recent study reports certain biallelic missense variants to result in loss of Gβ5 protein function leading to phenotypes more in keeping with IDDCA [16]. The evidence from Gnb5-knockout models (zebrafish and mice) demonstrated neuronal and cardiac phenotypes observed in IDDCA and LADCI patients [12,18,19,20,21]

Methods

Results

Discussion

Conclusion