DOK7 – Fetal Akinesia Deformation Sequence 1

DOK7 encodes a cytoplasmic adaptor essential for MuSK activation and neuromuscular junction (NMJ) formation. While biallelic loss-of-function variants in DOK7 are a well-established cause of congenital myasthenic syndrome, reports in lethal fetal akinesia deformation sequence (FADS) are emerging, defining a severe allelic‐related phenotype. The first family was described in 2020, and two additional unrelated consanguineous families have since been reported, expanding the clinical spectrum of DOK7 deficiency ([PMID:31880392]; [PMID:37849383]).

Inheritance of FADS due to DOK7 is autosomal recessive. To date, three unrelated probands have been documented with homozygous frameshift variants: c.1263dup (p.Ser422fs) and c.1378dup (p.Gln460fs), demonstrating complete loss of Dok-7 function. No extended segregation beyond parental carrier status has been reported.

Functional studies in zebrafish and murine models recapitulate the lethal phenotype seen in human FADS. Dok-7 deficiency abrogates early acetylcholine receptor clustering and disrupts NMJ morphology, leading to profound fetal akinesia and prenatal lethality ([PMID:20147321]). These data confirm haploinsufficiency is insufficient to drive this phenotype, supporting a complete loss-of-function mechanism.

Assessment of Clinical Validity

ClinGen Classification: Moderate

Rationale: Three unrelated probands with biallelic loss-of-function variants in DOK7; consistent autosomal recessive inheritance; supportive animal model data demonstrating concordant severe phenotype.

Genetic Evidence

ClinGen Tier: Moderate

Rationale: Three probands from three consanguineous families with homozygous frameshift variants (c.1263dup (p.Ser422fs); c.1378dup (p.Gln460fs)) establishing case-level allele evidence.

Functional Evidence

ClinGen Tier: Moderate

Rationale: Zebrafish Dok-7 knockdown and mouse knockout models reproduce the lethal akinesia and NMJ defects observed in human FADS, confirming the pathogenic mechanism.

Integration and Conclusion

Biallelic loss-of-function variants in DOK7 cause a lethal autosomal recessive fetal akinesia deformation sequence. The genetic and experimental evidence collectively support a Moderate level of confidence for this gene–disease association. This summary underscores the importance of including DOK7 in prenatal diagnostic panels for FADS and informs genetic counseling for at‐risk families.

Key Take-home: Biallelic frameshift DOK7 variants result in lethal FADS via complete loss of NMJ formation, warranting inclusion of DOK7 in prenatal genetic testing and family counseling.

References

• American journal of medical genetics. Part A • 2020 • Biallelic c.1263dupC in DOK7 results in fetal akinesia deformation sequence. PMID:31880392
• Clinical genetics • 2024 • Variants in DOK7 results in fetal akinesia deformation sequence: A case report and review of literature. PMID:37849383
• Human molecular genetics • 2010 • Dok-7 promotes slow muscle integrity as well as neuromuscular junction formation in a zebrafish model of congenital myasthenic syndromes. PMID:20147321

Evidence Based Scoring (AI generated)

Gene–Disease Association Moderate Three unrelated probands with biallelic LoF variants in DOK7; supportive animal model data Genetic Evidence Moderate Three probands from three consanguineous families with homozygous frameshift variants Functional Evidence Moderate Zebrafish and mouse knockout models reproduce lethal akinesia deformation