Intrafamilial Phenotypic Variability in SYNE1-Related Disorder

SYNE1 (OMIM 608441) encodes the spectrin repeat-containing nuclear envelope protein 1 (or synaptic nuclear envelope protein 1, nesprin 1), belonging to a family of proteins involved in connecting the nuclear plasma membrane to the actin cytoskeleton (Rajgor et al. 2012). SYNE1-related disorders (or SYNE1 deficiency) comprise a group of autosomal recessive or autosomal dominant inherited disorders with a broad range of phenotypes. The first reported phenotype was adult-onset spinocerebellar ataxia (also known as SCAR8 and ARCA1), with features including cerebellar ataxia, upper or lower motor neuron involvement, including spasticity and hyperreflexia, or conversely muscle atrophy and diminished reflexes, scoliosis, pes cavus, and varying degrees of cognitive impairment (Gros-Louis et al. 2007; Wiethoff et al. 2016). This entity has been referred to as recessive ataxia of Beauce, given it was originally identified in French-Canadian families originating from the Beauce and Bas-St-Laurent regions of Quebec (Gros-Louis et al. 2007), though it has since been identified in other diverse populations (Synofzik et al. 2016; Wiethoff et al. 2016). Biallelic SYNE1 pathogenic variants have now also been identified in patients with myogenic congenital arthrogryposis (Attali et al. 2009) and heterozygous pathogenic SYNE1 variants in Emery–Dreifuss muscular dystrophy (Zhang et al. 2007).

In the few familial cases published, affected individuals in the same family have had similar phenotypes, leading to a presumption of at least some genotype–phenotype correlation (Baumann et al. 2017; Synofzik et al. 2016; Wiethoff et al. 2016; Yucesan et al. 2017). Here, we present a family in which three affected individuals all had markedly different clinical presentations, highlighting the potential for intrafamilial phenotypic variability in SYNE1-related disorders.

Three siblings, aged 11, 13, and 15 years, were all found to carry the same biallelic frameshift pathogenic variants in SYNE1 (pedigree in Figure 1). The family is of Moroccan-Jewish ancestry, and parents were not known to be consanguineous. There was no other known family history of neurologic disease beyond the patients discussed here. Written consent for publication was obtained from the patients' parents. The study was approved by the McGill University Health Centre Research Ethics Board (2018-3937).

The proband is a now 13-year-old boy who was the product of a normal pregnancy except for right hydronephrosis on prenatal ultrasound that resolved by birth. He was delivered via Caesarean section at term, without any need for resuscitation. He had oral aversion and failure to thrive at 12 months, requiring nasogastric support for feeds for 2 years leading to eventual temporary gastrostomy tube placement despite no clinical concern for choking or formal swallowing assessment. The gastrostomy tube was eventually removed once taking adequate nutrition orally; he later developed obesity. He has pes cavus but tibialis anterior electromyography and nerve conduction studies (median, ulnar, and tibial nerves) did not demonstrate evidence of peripheral nerve or muscle involvement. Serum creatine kinase at age 14 months was only borderline elevated (287 U/L, laboratory reference range 41–277 U/L). He had delayed gross motor milestones, only walking after 3 years of age. He also has language impairment, only capable of saying a few words despite speech therapy, though with full understanding in two languages. He has a diagnosis of intellectual disability and attends a specialized school. Initial investigations, including Fragile X testing, chromosomal microarray and metabolic screen were negative, and brain and spine MRI were normal. He developed focal seizures at age 12 years, which were controlled on clobazam. In addition to pes cavus, his examination was notable for bilateral dysmetria, brisk deep tendon reflexes, difficulty with fine finger movements, and difficulty walking on heels and toes, though segmental strength was normal. A GeneDx Autism/ID Xpanded gene panel identified novel biallelic frameshift variants in SYNE1 (NM_033071.3): c.18309del, p.(Ser6104Alafs*30) (paternally-inherited) and c.18434del, p.(Leu6145Argfs*22) (maternally-inherited). Both variants are absent in the Genome Aggregation Database and classified “pathogenic” or “likely pathogenic” by American College of Medical Genetics and Genomics criteria (PVS1 and PM2 for both; PM3 for the c.18309del variant) (Chen et al. 2024; Richards et al. 2015).

His 15-year-old sister had normal early gross and fine motor developmental milestones, with mild language delay for which she was followed by speech/language pathology for a year. At age 10 years, she presented with multiple cranial neuropathies (including left cranial nerve IV and VI) and increased intracranial pressure of unclear etiology. A brain MRI showed enhancement along multiple bilateral cranial nerves and minimal leptomeningeal enhancement. Though not confirmed, there was suspicion for neurosarcoidosis. She was treated with prednisone and symptoms resolved. She was seen again at age 15 years for tension-type headache. Her exam at that time was notable for left dysmetria and difficulty with tandem gait. A repeat MRI brain was done which was normal. Considering her brother's diagnosis, genetic testing was conducted which identified the same two SYNE1 pathogenic variants.

The younger sister, an 11-year-old girl, is the product of an unremarkable pregnancy, born via Caesarean section without need for resuscitation. She had talipes equinovarus at birth for which she had surgery. Her early gross and fine motor development was within normal limits. Though she babbled at the expected age, she required speech therapy in infancy/early childhood, with difficulties in written language. At her elementary school, she has supports in place, such as using a computer to write. She is otherwise healthy. In clinic, her exam was notable for hyperreflexia in her lower extremities, upper extremity postural tremor bilaterally, but no ataxia, dysdiadochokinesia, or dysmetria. She had normal strength and sensation. Her brain MRI was normal. Genetic testing identified the same SYNE1 pathogenic variants found in her siblings.

There are two other siblings, a 16-year-old sister and a 10-year-old brother, who are asymptomatic and therefore genetic testing has not been carried out. The family was referred for genetic counseling.

This family includes multiple individuals with SYNE1-related disorders overall fitting best with SCAR8; however, the disparate clinical presentations demonstrate the potential for interindividual phenotypic variability, even with the same genotype. One patient has global developmental impairment, infantile failure to thrive, focal epilepsy, pes cavus, and mild cerebellar signs, a second has normal intelligence and mild cerebellar signs, and a third has congenital talipes equinovarus and mild language delay. This is a departure from most previously reported families in which intrafamilial phenotypes have been more homogeneous (Baumann et al. 2017; Synofzik et al. 2016; Wiethoff et al. 2016; Yucesan et al. 2017).

The finding of focal epilepsy in the proband is also significant, as seizures have only been reported in one previous patient with a SYNE1-related disorder, a female with cerebellar ataxia who had seizures at age 2 years (no further details were given) (Synofzik et al. 2016). The finding of epilepsy in our patient suggests that the previous association was not coincidental, though seizures still appear to be a rare entity in this genetic condition.

The 15-year-old sibling was treated for a diagnosis of possible neurosarcoidosis. While it is unusual that she be diagnosed with two rare entities, they are likely unrelated as her initial inflammatory symptoms resolved completely which would be unexpected with a neurogenetic condition.

Interestingly, despite clinical symptoms, all three individuals had normal brain MRI, while most previously reported patients have had cerebellar atrophy (Synofzik et al. 2016; Wiethoff et al. 2016). This may be explained by the young age and mild cerebellar symptoms in our patients, as cerebellar atrophy may still become apparent in the future.

With respect to genotype–phenotype correlation, Baumann et al. (2017) had noted that patients with congenital arthrogryposis had nonsense or splice site pathogenic variants that terminated in the C-terminal Klarsicht-ANC-Syne homology (KASH) domain and are predicted to affect at least the major muscle-specific nesprin-1-alpha-2 isoform. Although one of our patients had congenital talipes equinovarus (a congenital joint deformity, but distinct from the congenital arthrogryposis multiplex cases previously published), neither of the SYNE1 pathogenic variants identified in our family terminate in the KASH domain; both terminate in the chromosome segregation protein SMC, common bacterial type (SMC_prok_B) domain which has thus far been mainly associated with cerebellar ataxia phenotypes (Beaudin et al. 1993).

In summary, the findings in this family demonstrate that there can be marked intrafamilial phenotypic variability with SYNE1-related disorders, with phenotypes including non-ataxia features such as focal epilepsy and talipes equinovarus.

This study was approved by the McGill University Health Centre Research Ethics Board (2018-3937).

Written consent for publication was obtained from the patients' parents.

H.P. has no relevant disclosures. K.A.M. is a member of an advisory board for Jazz Pharmaceuticals.