Five Substitutions in Dolichol Kinase that Cause Congenital Defects in Glycosylation and Dilated Cardiomyopathy

Five Substitutions in Dolichol Kinase that Cause Congenital Defects in Glycosylation and Dilated Cardiomyopathy

Introduction:
Dolichol kinase (DOLK) plays a crucial role in protein glycosylation, and mutations in this gene can cause congenital disorders of glycosylation (CDG), resulting in multi-systemic effects, including severe heart issues like dilated cardiomyopathy (DCM). The following cases highlight five key DOLK substitutions associated with congenital defects, identified and compiled using Adenine AI, a tool that helps find genetic evidence for clinical application.

1. DOLK:c.1342G>A (p.Gly448Arg) and DOLK:c.1558A>G (p.Thr520Ala)

   • Phenotype: Neonatal ichthyosis, dilated cardiomyopathy, microcephaly, hepatic hemosiderosis, and early death
   • Age/Sex/Ethnicity: Neonatal, Sibling (male/female), Middle Eastern, Compound Heterozygous
   • Unique characteristic: Fatal neonatal ichthyosis with multisystem involvement, including cardiac dysfunction.
     PMID: 34956305

2. DOLK:c.1447C>A (p.Gln483Lys)

   • Phenotype: Dysmorphic features, severe seizures, dilated cardiomyopathy, renal failure, insulin-resistant hyperglycemia
   • Age/Sex/Ethnicity: Male neonate, Palestinian, Homozygous
   • Unique characteristic: Fatal multi-system metabolic and structural complications by 9 months of age.
     PMID: 24144945

3. DOLK:c.1222C>G (p.His408Asp)

   • Phenotype: Dilated cardiomyopathy, heart failure, leading to heart transplantation or death
   • Age/Sex/Ethnicity: Children (5–13 years), Israeli (Druze), Male/Female
   • Report also describe a Arabian family with homozygous DOLK:c.912G>T (p.Trp304Cys)
     PMID: 22327749

4. DOLK:c.912G>T (p.Trp304Cys)

   • Phenotype: Mild to moderate dilated cardiomyopathy, failure to thrive, ichthyosiform dermatitis
   • Age/Sex/Ethnicity: Multiple children (including 9 years male), Bedouin, Homozygous
   • Unique characteristic: Observed in consanguineous families with dermatological and cardiac manifestations.
     PMID: 22242004

Conclusion:
These five DOLK substitutions demonstrate the diverse clinical outcomes associated with CDG, from neonatal ichthyosis to dilated cardiomyopathy in older children. Early identification and genetic diagnosis are essential for managing these severe disorders. While Adenine AI doesn't provide testing, it supports clinicians in quickly gathering the genetic evidence needed for effective diagnosis and treatment planning.