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Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence.

Tan-Sindhunata MB, Mathijssen IB, Smit M, Baas F, de Vries JI, van der Voorn JP, Kluijt I, Hagen MA, Blom EW, Sistermans E, Meijers-Heijboer H, Waisfisz Q, Weiss MM, Groffen AJ - Eur. J. Hum. Genet. (2014)

Bottom Line: The carrier frequency in the genetic isolate was 8%, exclusively found in heterozygous carriers.Consistent with the established role of MUSK as a tyrosine kinase that orchestrates neuromuscular synaptogenesis, the fetal myopathy was accompanied by impaired acetylcholine receptor clustering and reduced tyrosine kinase activity at motor nerve endings.Taken together, the results strongly support a causal role of this founder mutation in MUSK, further expanding the gene set associated with FADS and offering new opportunities for prenatal genetic testing.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.

ABSTRACT
Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. FADS can result from mutations in CHRNG, CHRNA1, CHRND, DOK7 and RAPSN; however, these genes only account for a minority of cases. Here we identify MUSK as a novel cause of lethal FADS. Fourteen affected fetuses from a Dutch genetic isolate were traced back to common ancestors 11 generations ago. Homozygosity mapping in two fetuses revealed MUSK as a candidate gene. All tested cases carried an identical homozygous variant c.1724T>C; p.(Ile575Thr) in the intracellular domain of MUSK. The carrier frequency in the genetic isolate was 8%, exclusively found in heterozygous carriers. Consistent with the established role of MUSK as a tyrosine kinase that orchestrates neuromuscular synaptogenesis, the fetal myopathy was accompanied by impaired acetylcholine receptor clustering and reduced tyrosine kinase activity at motor nerve endings. A functional assay in myocytes derived from human fetuses confirmed that the variant blocks MUSK-dependent motor endplate formation. Taken together, the results strongly support a causal role of this founder mutation in MUSK, further expanding the gene set associated with FADS and offering new opportunities for prenatal genetic testing.

No MeSH data available.


Related in: MedlinePlus

Macroscopic appearance of four fetuses homozygous for the c.1724T>C; p.(Ile575Thr) variant in MUSK. (a) Case 6, stillborn at a gestational age of 33 weeks; (b) case 8, termination of pregnancy at 23 weeks; (c) case 10, died immediately after birth at 32 weeks; (d) case 11, termination of pregnancy at 22 weeks. Note the multiple contractures, facial appearance of hypertelorism and micro-retrognathia, club feet (b–d), oligodactyly of the right foot (c), plantar flexion of the feet (a). For details see Table 1. Bars indicate 5 cm.
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fig2: Macroscopic appearance of four fetuses homozygous for the c.1724T>C; p.(Ile575Thr) variant in MUSK. (a) Case 6, stillborn at a gestational age of 33 weeks; (b) case 8, termination of pregnancy at 23 weeks; (c) case 10, died immediately after birth at 32 weeks; (d) case 11, termination of pregnancy at 22 weeks. Note the multiple contractures, facial appearance of hypertelorism and micro-retrognathia, club feet (b–d), oligodactyly of the right foot (c), plantar flexion of the feet (a). For details see Table 1. Bars indicate 5 cm.

Mentions: The clinical symptoms available from 14 affected fetuses are summarized in Table 1. Pictures of four fetuses are shown in Figure 2. The pregnancy was terminated in three fetuses, whereas the natural course of the pregnancy was followed in 11 fetuses. From the naturally born fetuses, seven were born prematurely between 31–37 weeks of gestation and four were born at term. All 11 were stillborn or died shortly after birth, usually after failed resuscitation. Typical prenatal ultrasound findings were polyhydramnios, progressively reduced fetal movements and joint contractures. The polyhydramnios generally developed in the second or third trimesters, and became severely pronounced around 30 weeks, sometimes leading to premature rupture of membranes or premature contractions. Post-mortem examination revealed severe pulmonary hypoplasia in all cases. Hypertelorism, low-set ears, micrognathia and reduced muscle bulk were seen in most fetuses. The contractures could affect all joints with variable severity; however, all fetuses had contractures of the fingers (camptodactyly) and 10 out of 13 analyzed fetuses had severely affected feet (club feet, plantar flexion or rocker-bottom feet). Two fetuses who died 4 and 5 days after birth were severely hypotonic. All male fetuses had cryptorchidism, although this may not be representative because most children were born prematurely. Three of twelve analyzed fetuses were mildly edematous. Gracile ribs were observed in two cases. Some additional findings were observed only in a single fetus and are considered to be incidental: cervical ribs, mild ventriculomegaly, choroid plexus cysts, a solitary hemivertebra, syndactyly of the first and second toes and agenesis of the third toe. None of the fetuses had pterygia or a cleft palate.


Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence.

Tan-Sindhunata MB, Mathijssen IB, Smit M, Baas F, de Vries JI, van der Voorn JP, Kluijt I, Hagen MA, Blom EW, Sistermans E, Meijers-Heijboer H, Waisfisz Q, Weiss MM, Groffen AJ - Eur. J. Hum. Genet. (2014)

Macroscopic appearance of four fetuses homozygous for the c.1724T>C; p.(Ile575Thr) variant in MUSK. (a) Case 6, stillborn at a gestational age of 33 weeks; (b) case 8, termination of pregnancy at 23 weeks; (c) case 10, died immediately after birth at 32 weeks; (d) case 11, termination of pregnancy at 22 weeks. Note the multiple contractures, facial appearance of hypertelorism and micro-retrognathia, club feet (b–d), oligodactyly of the right foot (c), plantar flexion of the feet (a). For details see Table 1. Bars indicate 5 cm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4538208&req=5

fig2: Macroscopic appearance of four fetuses homozygous for the c.1724T>C; p.(Ile575Thr) variant in MUSK. (a) Case 6, stillborn at a gestational age of 33 weeks; (b) case 8, termination of pregnancy at 23 weeks; (c) case 10, died immediately after birth at 32 weeks; (d) case 11, termination of pregnancy at 22 weeks. Note the multiple contractures, facial appearance of hypertelorism and micro-retrognathia, club feet (b–d), oligodactyly of the right foot (c), plantar flexion of the feet (a). For details see Table 1. Bars indicate 5 cm.
Mentions: The clinical symptoms available from 14 affected fetuses are summarized in Table 1. Pictures of four fetuses are shown in Figure 2. The pregnancy was terminated in three fetuses, whereas the natural course of the pregnancy was followed in 11 fetuses. From the naturally born fetuses, seven were born prematurely between 31–37 weeks of gestation and four were born at term. All 11 were stillborn or died shortly after birth, usually after failed resuscitation. Typical prenatal ultrasound findings were polyhydramnios, progressively reduced fetal movements and joint contractures. The polyhydramnios generally developed in the second or third trimesters, and became severely pronounced around 30 weeks, sometimes leading to premature rupture of membranes or premature contractions. Post-mortem examination revealed severe pulmonary hypoplasia in all cases. Hypertelorism, low-set ears, micrognathia and reduced muscle bulk were seen in most fetuses. The contractures could affect all joints with variable severity; however, all fetuses had contractures of the fingers (camptodactyly) and 10 out of 13 analyzed fetuses had severely affected feet (club feet, plantar flexion or rocker-bottom feet). Two fetuses who died 4 and 5 days after birth were severely hypotonic. All male fetuses had cryptorchidism, although this may not be representative because most children were born prematurely. Three of twelve analyzed fetuses were mildly edematous. Gracile ribs were observed in two cases. Some additional findings were observed only in a single fetus and are considered to be incidental: cervical ribs, mild ventriculomegaly, choroid plexus cysts, a solitary hemivertebra, syndactyly of the first and second toes and agenesis of the third toe. None of the fetuses had pterygia or a cleft palate.

Bottom Line: The carrier frequency in the genetic isolate was 8%, exclusively found in heterozygous carriers.Consistent with the established role of MUSK as a tyrosine kinase that orchestrates neuromuscular synaptogenesis, the fetal myopathy was accompanied by impaired acetylcholine receptor clustering and reduced tyrosine kinase activity at motor nerve endings.Taken together, the results strongly support a causal role of this founder mutation in MUSK, further expanding the gene set associated with FADS and offering new opportunities for prenatal genetic testing.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.

ABSTRACT
Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. FADS can result from mutations in CHRNG, CHRNA1, CHRND, DOK7 and RAPSN; however, these genes only account for a minority of cases. Here we identify MUSK as a novel cause of lethal FADS. Fourteen affected fetuses from a Dutch genetic isolate were traced back to common ancestors 11 generations ago. Homozygosity mapping in two fetuses revealed MUSK as a candidate gene. All tested cases carried an identical homozygous variant c.1724T>C; p.(Ile575Thr) in the intracellular domain of MUSK. The carrier frequency in the genetic isolate was 8%, exclusively found in heterozygous carriers. Consistent with the established role of MUSK as a tyrosine kinase that orchestrates neuromuscular synaptogenesis, the fetal myopathy was accompanied by impaired acetylcholine receptor clustering and reduced tyrosine kinase activity at motor nerve endings. A functional assay in myocytes derived from human fetuses confirmed that the variant blocks MUSK-dependent motor endplate formation. Taken together, the results strongly support a causal role of this founder mutation in MUSK, further expanding the gene set associated with FADS and offering new opportunities for prenatal genetic testing.

No MeSH data available.


Related in: MedlinePlus