What are the management and follow-up recommendations for a patient who is heterozygous for TMEM67 (transmembrane protein 67) and VPS13B (vacuolar protein sorting 13 homolog B) mutations?

Management of Heterozygous VPS13B Carrier Status

A patient who is heterozygous for VPS13B requires no specific clinical management or surveillance, as heterozygous carriers of VPS13B mutations are phenotypically normal and do not develop Cohen syndrome. 1

Genetic Counseling and Family Planning

Genetic counseling is essential to discuss inheritance patterns and reproductive implications. 1

• VPS13B-related Cohen syndrome follows an autosomal recessive inheritance pattern, meaning disease manifestation requires biallelic (two copies) pathogenic variants 1, 2
• Heterozygous carriers have one normal copy of the gene, which provides sufficient protein function to prevent any clinical manifestations 1
• The primary concern is reproductive risk: if the patient's partner is also a carrier of a VPS13B mutation, each pregnancy has a 25% chance of producing an affected child with Cohen syndrome 1

Partner testing should be offered if the patient is planning pregnancy or is currently pregnant. 1

• If the partner tests negative for VPS13B mutations, offspring will either be carriers or unaffected, with no risk of Cohen syndrome 1
• If the partner is also a carrier, prenatal diagnostic options including chorionic villus sampling (10-12 weeks) or amniocentesis (15-18 weeks) should be discussed 3
• Pre-implantation genetic diagnosis represents an alternative reproductive option for carrier couples 1

Clinical Surveillance Recommendations

No routine clinical monitoring or specialty referrals are indicated for heterozygous VPS13B carriers. 1

• Heterozygous carriers do not require ophthalmologic evaluation, as retinal dystrophy only occurs in individuals with biallelic VPS13B mutations 4, 5
• Developmental screening, cognitive assessment, and growth monitoring are not necessary, as these features are exclusive to Cohen syndrome patients with two pathogenic variants 2, 4
• Cardiac, endocrine, or other organ system surveillance is not warranted in carrier individuals 1

Family Cascade Screening

First-degree relatives should be offered genetic testing to identify additional carriers for family planning purposes. 1

• Parents of the heterozygous individual should undergo testing, as one parent must also be a carrier (assuming de novo mutation has been excluded) 1
• Siblings have a 50% chance of being carriers if one parent is affected, or 25% if both parents are carriers 1
• Testing should be accompanied by pre-test genetic counseling explaining the implications of carrier status 1

Documentation and Variant Classification

The specific VPS13B variant should be documented using standard nomenclature with clear pathogenicity classification per ACMG guidelines. 6

• Variants should be classified as pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, or benign 1
• If the variant is classified as a VUS, clinical correlation with family history and periodic reclassification may be warranted as new data emerges 1
• Large deletions encompassing VPS13B exons have been reported and may require specialized testing methods beyond standard sequencing 2

Important Caveats

Heterozygous status for TMEM67 (mentioned in the original question) follows similar principles, as TMEM67-related ciliopathies are also autosomal recessive. 1, 7, 8

• Compound heterozygosity for variants in different ciliopathy genes does not typically cause disease, as each gene functions independently 1
• However, if clinical features suggestive of ciliopathy are present, further evaluation may be warranted to exclude digenic inheritance or other genetic causes 1