Recessive TMEM167A variants cause neonatal diabetes, microcephaly, and epilepsy syndrome.

Summary

Genome sequencing in six patients identified biallelic TMEM167A variants as a new genetic cause of MEDS, with universal neonatal diabetes and severe microcephaly and frequent epilepsy. Functional studies in EndoC-βH1 and iPSC-derived β cells showed that TMEM167A loss or a patient variant impairs ER-to-Golgi trafficking, sensitizes β cells to ER stress, disrupts proinsulin trafficking, and causes β-cell dysfunction.

Key Findings

• Six individuals with biallelic TMEM167A variants had neonatal diabetes and severe microcephaly; five had epilepsy.
• TMEM167A is highly expressed in human pancreas and brain.
• TMEM167A knockdown or patient p.Val59Glu variant increased β-cell ER stress sensitivity and impaired proinsulin trafficking to the Golgi.
• iPSC-derived β cells carrying p.Val59Glu exhibited functional defects consistent with diabetes.

Clinical Implications

Adds TMEM167A to genetic panels for neonatal diabetes/MEDS, enabling earlier diagnosis and counseling; suggests ER-stress–targeted strategies could be explored for β-cell protection.

Limitations

• Small patient cohort (n=6) limits generalizability and phenotype spectrum
• Lack of in vivo animal modeling to assess systemic and developmental impacts

Future Directions

Expand cohort studies to define penetrance and spectrum; develop animal models; explore ER-stress modulators or trafficking-corrective strategies as potential therapeutics.