Submission Details

DOK7 first reported in relation to autosomal recessive congenital myasthenic syndrome 10 in 2006 (Beeson et al., PMID: 16917026). Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Deleterious variants in DOK7 cause defective activation of the MuSK protein. This results in a less stable NMJ that are reduced in siz, which reduces signaling between nerve and muscle cells. Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. CMS10 is an autosomal recessive CMS resulting from a postsynaptic defect affecting endplate maintenance of the NMJ where DOK7 transcripts begin to be expressed in embryonic development and continue through adulthood. The majority of patients present with limb-girdle weakness in the first decade, though some cases present later in adulthood.

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms, inheritance pattern, and phenotypic variability occurred across a continuous spectrum. Therefore, the following disease entities have been lumped into one disease entity: Fetal akinesia deformation sequence 3 (OMIM:618389) and Myasthenic syndrome, congenital, 10 (OMIM: 254300).

Sixteen variants (missense, in-frame indel, frameshift) that have been reported in sixteen probands in two publications (PMIDs: 16917026, 18626973) are included in this curation.

The variant NM_173660.5:c.1124_1127dup (CA249193) reoccurred several times in this curation across multiple publications. Beeson et al., found a group of twenty-one individuals (sixteen of which had at least one copy of the variant NM_173660.5:c.1124_1127dup (CA249193)) with DOK7 mutations that caused CMS clinical features. Other variants in DOK7 for the cohort were: c.1339 _1342dup (p.Gly448Alafs Ter?), c.1263dup (p.Ser422LeufsTer?), c.548_551del (p.Phe183CysfsTer?), c.539G>C (p.Gly180Ala), c.1143dup (p.Glu382ArgfsTer25), c.1378dup (p.Gln460ProfsTer?), c.1508dup (p.Pro504SerfsTer15), c.1361_1374del (p.Leu454ProfsTer?), c.601C>T (p.Arg201Ter). The cohort shared clinical features such as weakness of facial musculature, proximal muscle weakness in upper limbs, proximal muscle weakness in lower limbs, ptosis, gait disturbance, and generalized muscle weakness. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.

This gene-disease relationship is also supported by experimental evidence (animal models) (PMIDs: 25237101, 16794080). Arimura et al. used DOK7-transgenic mice (Tg) to overexpress DOK7 uniformly throughout the skeletal muscle under control of the human skeletal a-actin promoter. While forced expression enhanced the activation of muscle specific kinase (MuSK) and neuromuscular junction (NMJ) formation, DOK7-Tg mice did not exhibit obvious motor defects. Okada et al. (PMID: 16794080), showed the regulatory interaction of DOK7 with a known MuSK mutant (Val790Met) and concluded neuromuscular synaptogenesis requires DOK7 within the skeletal muscle. This follows that DOK7 dysfunction may be involved in the pathogenesis of neuromuscular junction disorders. Functional studies in patient and non-patient cells also show that DOK7 plays a role in propper AChR clustering (PMIDs: 36579833, 32043676). Rescue studies indicate that forced expression of a DOK7 transgene, specifically in skeletal muscle, restored survival and motor activity of DOK7 myasthenic mice (PMID: 25237101).

In summary, there is definitive evidence supporting the relationship between DOK7 and autosomal recessive congenital myasthenic syndrome 10 . This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Congenital Myopathies GCEP on the meeting date January 27th 2025 (SOP Version 11).

Data provided by the ClinGen Prenatal GCEP from February 20, 2025 secondary analysis: A limited cohort (9 probands 5 families - some with incomplete phenotypic information) shows that Congenital myasthenic syndrome 10 can be prenatally identified by fetal imaging. The prenatal findings include non-immune hydrops fetalis (n=4), contractures (n=9), intrauterine/neonatal death (n=6), pulmonary hypoplasia (n=3). There is variable presentation with the same genotypes reported in both fetal onset and later onset patients (PMID 19261599; 33820833; 31880392; 37849383).

DOK7 first reported in relation to autosomal recessive congenital myasthenic syndrome 10 in 2006 (Beeson et al., PMID: 16917026). Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Deleterious variants in DOK7 cause defective activation of the MuSK protein. This results in a less stable NMJ that are reduced in siz, which reduces signaling between nerve and muscle cells. Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. CMS10 is an autosomal recessive CMS resulting from a postsynaptic defect affecting endplate maintenance of the NMJ where DOK7 transcripts begin to be expressed in embryonic development and continue through adulthood. The majority of patients present with limb-girdle weakness in the first decade, though some cases present later in adulthood.

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms, inheritance pattern, and phenotypic variability occurred across a continuous spectrum. Therefore, the following disease entities have been lumped into one disease entity: Fetal akinesia deformation sequence 3 (OMIM:618389) and Myasthenic syndrome, congenital, 10 (OMIM: 254300).

Sixteen variants (missense, in-frame indel, frameshift) that have been reported in sixteen probands in two publications (PMIDs: 16917026, 18626973) are included in this curation.

The variant NM_173660.5:c.1124_1127dup (CA249193) reoccurred several times in this curation across multiple publications. Beeson et al., found a group of twenty-one individuals (sixteen of which had at least one copy of the variant NM_173660.5:c.1124_1127dup (CA249193)) with DOK7 mutations that caused CMS clinical features. Other variants in DOK7 for the cohort were: c.1339 _1342dup (p.Gly448Alafs Ter?), c.1263dup (p.Ser422LeufsTer?), c.548_551del (p.Phe183CysfsTer?), c.539G>C (p.Gly180Ala), c.1143dup (p.Glu382ArgfsTer25), c.1378dup (p.Gln460ProfsTer?), c.1508dup (p.Pro504SerfsTer15), c.1361_1374del (p.Leu454ProfsTer?), c.601C>T (p.Arg201Ter). The cohort shared clinical features such as weakness of facial musculature, proximal muscle weakness in upper limbs, proximal muscle weakness in lower limbs, ptosis, gait disturbance, and generalized muscle weakness. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.

This gene-disease relationship is also supported by experimental evidence (animal models) (PMIDs: 25237101, 16794080). Arimura et al. used DOK7-transgenic mice (Tg) to overexpress DOK7 uniformly throughout the skeletal muscle under control of the human skeletal a-actin promoter. While forced expression enhanced the activation of muscle specific kinase (MuSK) and neuromuscular junction (NMJ) formation, DOK7-Tg mice did not exhibit obvious motor defects. Okada et al. (PMID: 16794080), showed the regulatory interaction of DOK7 with a known MuSK mutant (Val790Met) and concluded neuromuscular synaptogenesis requires DOK7 within the skeletal muscle. This follows that DOK7 dysfunction may be involved in the pathogenesis of neuromuscular junction disorders. Functional studies in patient and non-patient cells also show that DOK7 plays a role in propper AChR clustering (PMIDs: 36579833, 32043676). Rescue studies indicate that forced expression of a DOK7 transgene, specifically in skeletal muscle, restored survival and motor activity of DOK7 myasthenic mice (PMID: 25237101).

In summary, there is definitive evidence supporting the relationship between DOK7 and autosomal recessive congenital myasthenic syndrome 10 . This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Congenital Myopathies GCEP on the meeting date January 27th 2025 (SOP Version 11).