First Report of SYNE1 Arthrogryposis Multiplex Congenita From Saudi Arabia With a Novel Mutation: A Case Report

Introduction: Arthrogryposis multiplex congenita (AMC), is a rare congenital condition characterized by multiple joint contractures often affecting both arms and legs which start prior to birth. Patient concern: The pediatrician attending delivery noticed the baby being dysmorphic with generalized hypotonia and multiple joint contractures at birth with antenatal history of reduced fetal movement. The patient was admitted to the neonatal intensive care unit for strict observation and further work up. Diagnosis: Whole Exome Sequencing was performed and identied the novel homozygous variant in the synaptic nuclear envelope protein1 [SYNE1] gene. Intervention: Multidisciplinary team were involved in the management plan, supportive care was the mainstay of treatment. Outcomes: Due to feeding diculties and on and off requirement of oxygen support, the patient remained hospitalized for a long period then was discharged home on supplemental oxygen and gastrostomy tube feeding. Conclusions: AMC3 should be suspected in patients with decreased fetal movements, dysmorphic features, hypotonia, and arthrogryposis. Molecular testing of the SYNE1 gene conrms diagnosis.


Introduction
Arthrogryposis multiplex congenita (AMC), describe a variety of unprogressive skeletal defects with joint contractures found throughout the body, arms and legs are more commonly affected, presenting at birth. 1 Arthrogryposis is a rare condition. prevalence is one in 3000 in general population 2 it is less common in European population, occurring in 1 out of every 11000 -12000 live births 3 .
There is no single cause for AMC. Decreased fetal movement in utero is one known factor, which can occur due to variety of reasons, including environmental factors (i.e. maternal illness, limited space), gene mutation (autosomal dominant, autosomal recessive, X-linked), chromosomal abnormalities and various syndromes 4 Myogenic-type arthrogryposis multiplex congenita-3 (AMC3) is an autosomal recessive disorder characterized by decreased fetal movements, hypotonia, variable skeletal defects, including clubfoot and scoliosis, and delayed motor milestones with di culty walking 5 SYNE1 gene is found in many tissues, encodes nesprin-1, a member of the spectrin family of structural proteins that link the nuclear plasma membrane to the actin cytoskeleton. Mutations in this gene have been associated with multiple congenital conditions, one of them is Myogenic-type AMC3. 5 The present report describes a Saudi newborn baby boy with dysmorphic feature, hypotonia and multiple joint contractures, in whom Whole Exome Sequencing identi ed a novel homozygous variant c.23415-3799C G p.(?) in the SYNE1 gene (OMIM:608441).
Case Report SA is 6-month-old Saudi male who was born to a healthy rst-degree relatives Saudi cousins, with uneventful perinatal history, and negative family history of neuromuscular disease. He was delivered at term by elective cesarean section due to breech presentation, to a 30-year-old G4P3 mother.
He was admitted to the neonatal intensive care with respiratory distress, requiring intubation and positive pressure ventilation.
His examination revealed subtle dysmorphism in form of long narrow face, hirsutism long philtrum, depressed nasal bridge, at occiput, large ears along with generalized muscle wasting added to arthrogryposis multiplex in the upper & lower limbs, involving interphalangeal joint, metatarsophalangeal joint, thoraco-lumbar scoliosis, bilateral knee dislocation, bilateral club foot, clenched hand and overlapping ngers (Figures 1a-d).
Neurological examination showed generalized hypotonia and absent deep tendon re exes. Brain magnetic resonance imaging showed no abnormal ndings.
Echocardiogram showed small mid-muscular ventricular septal defect, and small patent ductus arteriosus with otherwise normal cardiac structure and function.
Abdominal examination showed no organomegaly, normal looking genitalia with bilateral undescended testis. His other body system review was unremarkable.
Laboratory investigations revealed normal complete blood count, renal and hepatic functions, normal electrolytes and normal creatinine kinase as well as metabolic screening. Karyotyping revealed a normal 46, XY karyotype.
Due to feeding di culties and intermittent requirement of oxygen support, he was discharged on gastrostomy tube feeding and home oxygen.

Mutation identi cation:
Molecular genetic analysis of whole exome sequencing was done ( Figure 2). Analysis: The coding exons of more than 20.000 genes of the patient DNA were enriched and sequenced.
Filtering of the exome data targeted recessive, X-linked and dominantly inherited diseases Result: Variant with signi cant phenotypic overlap in the proband was identi ed (Table 1). Considering the homozygous variant of uncertain signi cance in the SYNE1 gene, a genetic diagnosis of myogenic arthrogryposis multiplex congenita type 3 for the patient is possible.
For further interpretation of the results and to improve variant classi cation, segregation analysis of the identi ed variant in the parents and further affected and unaffected family members was done. It revealed that both parents and 1 apparently healthy sibling were carrying the same mutation in heterozygous status. Two other siblings were normal.
Secondary ndings (reported according to ACMG guidelines): No pathogenic or likely pathogenic variants were detected in the genes for which incidental ndings are reported based on the ACMG guidelines.

Discussion
The term arthrogryposis, or AMC, refers to a group of nonprogressive disorders characterized by multiple joint contractures discovered at birth in the body. 1 Review of the Saudi literature, arthrogryposis was occasionally described but with different gene mutation and clinical syndromes. The mutation identi ed in this paper is a novel mutation which was not reported before Saudi Arabia and has not been described in the literature so far.
Reviewing English literature revealed only ve reported cases with variable mutations in SYNE1 gene, with similar clinical manifestation. 5,6,7 Our patient is the sixth patient worldwide identi ed with an AMC-causing SYNE1 mutation.
Other than AMC; all patients shared some clinical ndings including reduced fetal movements, absence of polyhydramnios, no noticeable intrauterine growth retardation, and absence of associated malformations (Table 2). They have borderline to average intellectual growth and motor development is slightly delayed without creatinine kinase elevation (Table 2). The condition was progressive in one family of sib pairs that were unable to walk at 12 years of age and developed severe scoliosis, leading to death from pneumonia in one patient at 22 years of age. 7 There is no indication of cerebellar disease in these patients. While the progression of the disease is unpredictable, as ve out of six living patients are younger than 20 years.
Two reported sibs were reported in one paper with limited clinical details. 6

Conclusions
High index of suspicion is needed to diagnose AMC3 in patients with decreased fetal movements, dysmorphic features, hypotonia, and arthrogryposis. Molecular genetic analysis of the SYNE1 gene con rms diagnosis.

Declarations
Ethical Approval and Consent to participate: the study was approved by the research and ethical committee of the participating hospitals. All parents of enrolled children signed written informed consents for participation of their children in the current study.
'Written informed consent was obtained from the patient's legal guardian for the publication of any potentially identi able images or data included in this article.
Consent for publication: All parents of enrolled children signed written informed consents for publication the current study.
Availability of data and materials: all data and materials related to the study are included in the current manuscript.