Abstract and Introduction
Abstract
Background Fetal akinesia deformation sequence syndrome (FADS, OMIM 208150) is characterised by decreased fetal movement (fetal akinesia) as well as intrauterine growth restriction, arthrogryposis, and developmental anomalies (eg, cystic hygroma, pulmonary hypoplasia, cleft palate, and cryptorchidism). Mutations in components of the acetylcholine receptor (AChR) pathway have previously been associated with FADS.
Methods and results We report on a family with recurrent fetal loss, where the parents had five affected fetuses/children with FADS and one healthy child. The fetuses displayed no fetal movements from the gestational age of 17 weeks, extended knee joints, flexed hips and elbows, and clenched hands. Whole exome sequencing of one affected fetus and the parents was performed. A novel homozygous frameshift mutation was identified in muscle, skeletal receptor tyrosine kinase (MuSK), c.40dupA, which segregated with FADS in the family. Haplotype analysis revealed a conserved haplotype block suggesting a founder mutation. MuSK (muscle-specific tyrosine kinase receptor), a component of the AChR pathway, is a main regulator of neuromuscular junction formation and maintenance. Missense mutations in MuSK have previously been reported to cause congenital myasthenic syndrome (CMS) associated with AChR deficiency.
Conclusions To our knowledge, this is the first report showing that a mutation in MuSK is associated with FADS. The results support previous findings that CMS and/or FADS are caused by complete or severe functional disruption of components located in the AChR pathway. We propose that whereas milder mutations of MuSK will cause a CMS phenotype, a complete loss is lethal and will cause FADS.
Introduction
Fetal akinesia deformation sequence (FADS) (OMIM 208150), also known as Pena-Shokeir syndrome I or arthrogryposis multiplex congenita (AMC) with pulmonary hypoplasia, is a rare condition associated with malformations caused by reduced fetal movement (fetal akinesia). About 30% of affected individuals are stillborn and many live born infants survive only a short time due to complications of pulmonary hypoplasia.
FADS is characterised by arthrogryposis, fetal akinesia, intrauterine growth restriction, developmental abnormalities such as cystic hygroma, pulmonary hypoplasia, cleft palate, cryptorchidism, cardiac defects, intestinal malrotation and sometimes pterygia of the limbs. It shows phenotypic overlap with the lethal type of multiple pterygium syndrome (LMPS, OMIM 253290).
FADS is most often inherited as an autosomal recessive trait, but X-linked or dominant inheritance have also been suggested. Several mutations have been described in FADS and/or LMPS, explaining around 24% of the cases, and involving genes in the motor neuron development and survival, genes encoding components of the neuromuscular junction (NMJ), adult skeletal muscle proteins, and fetal myostructural proteins. The mutations located in genes associated with the NMJ include the subunits of the acetylcholine receptor (AChR): CHRNA1 (OMIM 100690),CHRND (OMIM 100720) and CHRNG (OMIM 100730); and genes signalling with muscle, skeletal receptor tyrosine kinase (MuSK) in the prepatterning process: RAPSN (OMIM 601592) and DOK7 (OMIM 610285). Mutations in SYNE1 (OMIM 608441), also involved in the prepatterning process, leads to AMC, and mutations in CNTN1 (OMIM 600016), a neural adhesion and NMJ protein, have been described to cause a congenital lethal myopathy (figure 1).
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Figure 1.
Fetal akinesia deformation sequence (FADS) and/or multiple pterygium syndrome (MPS) are associated with genes involved in the neuromuscular junction (NMJ). Several genes (CHRNA1, CHRND, CHRNG, RAPSN, DOK7, CNTN1 and SYNE1) involved in the NMJ have previously been associated with FADS. One additional gene, muscle, skeletal receptor tyrosine kinase (MuSK) (OMIM 601296) was identified that can be used in prenatal testing or genetic analysis for NMJ disorders.
Other non-lethal diseases involved in the NMJ pathway include congenital myasthenic syndrome (CMS, OMIM 608931) and Escobar syndrome (OMIM 265000). CMS can be classified as presynaptic, synaptic or postsynaptic. Approximately 75% of CMS cases are postsynaptic, the majority of which are caused by AChR deficiency.
The emergence of high throughput DNA sequencing technologies has made it possible to sequence more rapidly and less expensively the coding parts of a patient's genome, to enable unbiased searching for novel disease genes and identify potentially damaging mutations. We performed whole exome sequencing (WES) of a family trio, where the parents had five affected fetuses/children with a severe lethal form of FADS and one healthy child. Diagnosis of the fetuses was unknown until identification of the disease-causing gene was completed. This study reports a novel lethal homozygous insertion in the gene encoding MuSK. The frameshift mutation leads to a premature stop codon and likely a non-functional protein, causing the FADS phenotype.