Rhabdomyolysis and Metabolic Myopathy

Gene: KCNJ11

Red List (low evidence)

Single consanguineous family reported with congenital hyperinsulinism and rhabdomyolysis
Sources: Literature

Created: 29 May 2020, 4:44 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Hyperinsulinemic hypoglycemia, familial, 2 MIM#601820

Green List (high evidence)

Congenital hyperinsulinism (HI) variants are generally reported in heterozygous patients where they also carry a somatic 2nd hit, or have isodisomy of the paternal allele (focal HI), or in bilallelic patients (diffuse HI). This condition can be dominant (but rarely), where patients with these missense are diazoxide-responsive. Patients with recessively inherited variants are diazoxide-unresponsive (OMIM, PMID:11395395, PMID: 23275527, PMID: 23345197).

Genotype-phenotype correlation:
Permanent neonatal diabetes – GOF (OMIM)
Permanent neonatal diabetes + other features – GOF (OMIM)
Congenital hyperinsulinism – LOF (PMID:18250167).

PTCs - LOF
Missense - Loss and gain of function
LOF – cause reduce channel expression, channel activity and increase current decay (PMID:18250167)
GOF - impair ATP-based sensitivity, more open state channel (OMIM)

Mutations generally occur on the paternal allele (PMID: 23345197).

Created: 15 Apr 2020, 3:29 a.m. | Last Modified: 15 Apr 2020, 3:29 a.m.

Panel Version: 0.2280

Congenital hyperinsulinism (HI) variants are generally reported in heterozygous patients where they also carry a somatic 2nd hit, or have isodisomy of the paternal allele (focal HI), or in bilallelic patients (diffuse HI). This condition can be dominant (but rarely), where patients with these missense are diazoxide-responsive. Patients with recessively inherited variants are diazoxide-unresponsive (OMIM, PMID:11395395, PMID: 23275527, PMID: 23345197).

Genotype-phenotype correlation:
Permanent neonatal diabetes – GOF (OMIM)
Permanent neonatal diabetes + other features – GOF (OMIM)
Congenital hyperinsulinism – LOF (PMID:18250167).

PTCs - LOF
Missense - Loss and gain of function
LOF – cause reduce channel expression, channel activity and increase current decay (PMID:18250167)
GOF - impair ATP-based sensitivity, more open state channel (OMIM)

Mutations generally occur on the paternal allele (PMID: 23345197).

Created: 15 Apr 2020, 3:29 a.m. | Last Modified: 15 Apr 2020, 3:29 a.m.

Panel Version: 0.2280

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
{Diabetes mellitus, type 2, susceptibility to} 125853; Diabetes mellitus, transient neonatal, 3 610582; Diabetes, permanent neonatal, with or without neurologic features 606176; Hyperinsulinemic hypoglycemia, familial, 2 601820; Maturity-onset diabetes of the young, type 13 616329 AD

Publications

• PMID:18250167
• 11395395
• 23275527
• 23345197

Mode of pathogenicity
Other