SA is 6-month-old Saudi male who was born to a healthy first-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.
His Antenatal ultrasound scan showed reduced fetal movements. Apgar score was 5 and 7 at 1 and 5 minutes respectively. Birth weight was 2595g (50th centile) and occipitofrontal circumference was 37 cm (50th centile).
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, flat 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 fingers (Figures 1a-d).
Neurological examination showed generalized hypotonia and absent deep tendon reflexes. Brain magnetic resonance imaging showed no abnormal findings.
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 difficulties and intermittent requirement of oxygen support, he was discharged on gastrostomy tube feeding and home oxygen.
Mutation identification:
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 significant phenotypic overlap in the proband was identified (Table 1).
Table 1
Molecular genetic identification
Classification
|
MAF
GenomAD [%]
|
Zygosity
|
Variant
|
Phenotype MIM number (Mode of Inheritance)
|
Gene
( isoform )
|
Variant of Uncertain Significance
|
0
|
Hom.
|
c.23415-3799C>G
p.(?)
chr6.152489259
|
618484 (AR)
612998(AD)
610743 (AR)
|
SYNE1
(NM_033071.3)
|
Interpretation: WES identified the homozygous variant c.23415-3799C>G p.(?) in the SYNE1 gene (OMIM: 608441). This is a deep intronic variant with unclear consequence on protein sequence. However, based on another isoform of the gene (NM_001347702.1) the variant nomenclature is c.81C>G p.(Cys27Trp) which leads to an amino acid exchange.
Seven out of 20 bioinformatic in silico programs predict a pathogenic effect for this variant. To the best of our knowledge the variant has not been described in the literature so far (HGMD 2020.2).
Allele frequency of this variant in the general population has not been documented and this is the first time to be reported. Considering the available information, the variant is classified as variant of uncertain significance.
Pathogenic variants in the SYNE1 gene cause autosomal recessive myogenic arthrogryposis multiplex congenital type 3 (AMC3; OMIM: 618484) among others. AMC3 is characterized by decreased fetal movements, hypotonia, variable skeletal defects, including clubfoot and scoliosis, contractures, and delayed motor milestones with difficulty walking.
Considering the homozygous variant of uncertain significance 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 classification, segregation analysis of the identified 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 findings (reported according to ACMG guidelines):
No pathogenic or likely pathogenic variants were detected in the genes for which incidental findings are reported based on the ACMG guidelines.