Academy of Medical Sciences of I.R. Iran Archives of Iranian Medicine 1029-2977 27 12 2024 12 01 First Case of Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation Harboring Co-inherited Variants in HERC1 and PMP22 Genes from Iran: Two Novel Variants 700 706 10.34172/aim.31593 EN Azadeh Reshadmanesh https://orcid.org/0009-0004-2401-6602 Shima Dehdahsi https://orcid.org/0009-0005-8188-5019 Fatemeh Ahangari Kimia Kahrizi Ariana Kariminejad Shokouh Sadat Mahdavi Saeed Talebi https://orcid.org/0000-0002-8055-9335 Hossein Najmabadi https://orcid.org/0000-0002-6084-7778 Journal Article 10.34172/aim.31593 2024 07 01 2024 08 21 Here, we report a case with concomitant variants: a novel homozygous HERC1 gene variant and a novel heterozygous PMP22 duplication. The 2-year-old male presented with seizures, developmental delay, macrocephaly, hypotonia, unilateral hypertrophy, thoracic scoliosis, normal brain MRI, and elevated homocysteine level which normalized after treatment. Whole exome sequencing (WES) revealed a co-occurrence of a homozygous novel likely pathogenic variant in the HERC1 gene (NM_003922.3:c.1280dup (p.ILe469Aspfs*33) and a novel heterozygous large duplication of exon 1-5 in the PMP22 gene, which has not been reported previously. The case underscores the challenges in understanding genotype-phenotype correlations and suggests a potential interplay between these genetic variants in shaping the current and future clinical phenotype of the patient. In the case of genetic diseases, this event may have important implications on family members’ counseling, and concomitant variants in Charcot–Marie–Tooth (CMT) families should be considered when significant intra-familial clinical heterogeneity is observed.