Abstract
Holt-Oram syndrome (HOS; OMIM 142900 ) is a rare autosomal dominant disorder, typically involving upper limb anomalies and cardiac septal defects. HOS is caused by mutations in the TBX5 gene, which encodes a T-box transcription factor. We report a Japanese family with a novel TBX5 -Q469* nonsense variant that exhibited atypical HOS characteristics, including early-onset sick sinus syndrome (SSS), but no apparent upper limb abnormalities. The proband required a pacemaker implantation at age 44 for SSS and repeated catheter ablation procedures for atrial fibrillation (AF). His daughter experienced AF with pauses, requiring catheter ablation and a pacemaker. Neither exhibited upper limb abnormalities or cardiac structural defects. However, the 28-year-old granddaughter of the proband, who did not undergo genetic testing, had a surgically corrected atrial septal defect at the age of 5. She also exhibits mild shortening of the fifth finger and sinus bradycardia. This study expanded the phenotypic spectrum of HOS, emphasizing the potential for a TBX5 variant to present as familial early-onset SSS without overt skeletal anomalies. These findings highlighted the need for genetic screening for TBX5 variants in cases of early-onset familial SSS and congenital heart defects. Genetic screening may enhance early diagnosis and guide individualized management strategies.
Learning objective
Genetic testing for the TBX5 gene, the causal gene for Holt-Oram syndrome, should be considered in patients with a high prevalence of early-onset familial sick sinus syndrome and history of congenital heart disease. Even in atypical cases without obvious abnormalities of the upper extremities, this could enhance the diagnosis of Holt-Oram syndrome and guide individualized management strategies.
Introduction
Holt-Oram syndrome (HOS) (OMIM [Online Mendelian Inheritance in Man] #142900) is a rare autosomal dominant disorder with an estimated incidence of 1: 100,000 live births [ , ]. It is characterized by a combination of upper limb anomalies, congenital heart defects such as atrial septal defect (ASD) or ventricular septal defect (VSD), conduction disturbance and dilated cardiomyopathy (DCM) [ , ]. The syndrome is caused by mutations in the T-box transcription factor 5 ( TBX5 ) gene located on chromosome 12q24 [ ]. In vertebrates and humans, TBX5 is required for normal cardiac development, including cell specification, proliferation, differentiation, tissue patterning and morphogenesis. To date, >100 different TBX5 variants have been reported [ ], categorizing affected individuals into three groups: those with only skeletal abnormalities (27.4 %), those with only septal defects (3.9 %) and those with skeletal and cardiac abnormalities (68.7 %) [ ], and these cardiac and skeletal abnormalities exhibit a wide range of severity even among members of the same family. Recent studies have identified atypical cases of HOS characterized by predominant conduction disorders, minimal or no skeletal abnormalities, and low penetrance of congenital heart defects [ ]. Here, we report a Japanese family with a novel Q469*nonsense variant in the TBX5 gene, exhibiting an atypical form of HOS characterized by a high prevalence of early-onset sick sinus syndrome (SSS) without upper limb abnormalities. The proband’s granddaughter, who did not undergo genetic testing, had ASD. This study suggested an expanding clinical spectrum of TBX5 -related phenotypes in HOS and highlighted the importance of genetic testing that includes TBX5 in early-onset familial SSS and ASD even in the absence of overt upper limb abnormalities.
Methods
Genomic DNA was captured using a custom probe panel SeqCap EZ Choice Library (Roche) for 459 cardiovascular disease-related genes and sequenced on a Hiseq2500 platform (Illumina), and the raw sequence reads were aligned with the human reference genome (GRCh37) [ ]. After variation calling, rare variations with minor allele frequencies <0.1 % were filtered using public variation databases and validated by a polymerase chain reaction followed by Sanger sequencing. Additional details are provided in the supplemental file.
Case report
The proband (I-1), an 83-year-old male, underwent a VVI pacemaker implantation at the age of 44 for SSS (Rubenstein group III, tachycardia-bradycardia syndrome) ( Fig. 1 A ). At 66 years old, he was referred to our hospital for pacemaker management and was found to have persistent atrial fibrillation (AF). Genetic testing identified a nonsense variation in the TBX5 gene (chr.12:114793489 G > A, c.C1405T; p.Q469*: NM_000192.3) ( Fig. 1 B). This variant has been classified as PVS1 in accordance with the American College of Medical Genetics guidelines, indicating strong pathogenicity. Additionally, the variant is not listed in either the globally curated gnomAD database or the Japanese-specific ToMMo database, underscoring its rarity. In silico modeling with a CADD Phred score of 43 further supports the variant’s strong pathogenic impact. No other genes associated with cardiomyopathy or arrhythmia were identified. He underwent catheter ablation at age 67 and 80; however, AF recurred post-procedurally. Serial 12‑lead electrocardiograms (ECGs) indicated a progressive prolongation of the PR interval ( Fig. 1 C, D), without evidence of coved or saddleback-type ST-segment changes suggestive of Brugada syndrome (Supplementary file). The proband’s daughter (II-3) exhibited sinus bradycardia during adolescence. At age 37, Holter monitoring revealed a mean heart rate of 54 bpm, with a minimum of 32 bpm, along with episodes of paroxysmal AF characterized by pauses of up to 3 s after conversion ( Fig. 1 E). At 38 years of age, she underwent catheter ablation of AF and was prescribed flecainide to manage recurrent AF episodes detected by Holter monitoring. She was also diagnosed with mixed connective tissue disease; however, there was no evidence of systemic organ involvement. At 50 years old, she experienced ventricular fibrillation (VF) while undergoing a stress test to evaluate exercise-induced pulmonary hypertension during ongoing flecainide therapy ( Fig. 2 ). She was successfully resuscitated without complications, and flecainide was discontinued. At the age of 54, she experienced a syncopal episode caused by paroxysmal AF with a 7-s pause after conversion to sinus rhythm. Subsequently, she underwent catheter ablation for AF followed by the implantation of a DDD pacemaker. Remote pacemaker monitoring has not revealed any episodes of ventricular tachyarrhythmia or AF. Neither the proband (I-1) nor his daughter (II-3) had upper limb malformations or ASD. During 17 years of follow-up, neither showed any evidence of cardiac dysfunction. The 28-year-old granddaughter of the proband (III-3) did not undergo genetic testing but had a surgically corrected ASD at the age of 5 years. Physical examination revealed a tendency toward a short fifth finger, and a 12‑lead ECG revealed sinus bradycardia ( Fig. 3 ).
