Accessory breasts denote the formation of extra breast tissue along the milk line, and are known to be more prevalent among Black and Asian populations, affecting both genders. This first-ever study aimed to determine the genetic aetiology of accessory breasts in a multiplex family, where all female siblings present with bilateral accessory breasts. The study also ascertained secondary findings (SFs) responsible for comorbidities. Clinical data and saliva samples were obtained from all family members. Ultrasound and histopathology confirmed the diagnosis. Whole-exome sequencing was conducted on DNA samples obtained from the saliva, with variant calling conducted utilising the Sentieon workflow. Variant classification was based on American College of Medical Genetics and Genomics guidelines. After segregation analysis, 12 candidate genes emerged. Among these, PRSS50 and FANCC emerged as top candidates, being implicated in breast diseases. However, two variants in FANCC (c.360del; p.His120GlnfsTer24 and c.355_358del; p.Ser119IlefsTer24) were selected as the most probable causal variants because of the role of this gene in hereditary breast and ovarian cancer syndromes. The remaining ten genes were reported as potentially accounting for comorbidities segregating with accessory breasts. Reported SFs involve TTR and RYR1. In conclusion, pathogenic variants in FANCC cause familial accessory breasts. These novel observations impact pathophysiology, genetic counselling, and personalised medicine.

Background/Objectives: Orofacial clefts (OFCs) are among the most common birth defects globally, sometimes exacerbated by adverse drug reactions (ADRs) from corticosteroids and antiepileptics. Comprehending the pharmacogenomic and pharmacogenetic elements that lead to ADRs is essential for enhancing precision medicine and clinical outcomes. This study examines rare genetic variants in drug-metabolizing and drug-transporting genes among Ghanaian and Nigerian families with a history of OFCs, intending to assess their pathogenicity and functional implications. Methods: We recruited 104 Ghanaian families and 26 Nigerian families, generating whole-genome sequencing (WGS) data from 390 individuals (130 case-parent trios). DNA isolated from saliva and buccal swab samples underwent WGS, and subsequent WGS data were analyzed through extensive bioinformatics analyses. Variants were called and annotated using the GATK workflow. The HOPE in silico modeling tool evaluated the structural impact of genetic variants on encoded proteins, while molecular docking using PyRx examined alterations in ligand binding affinity. Results: Our study revealed pathogenic variants in vital genes associated with drug metabolism and transport, specifically CYP1A2, CYP2C18, CYP27A1, CYP2B6, SLC6A2, and ABCC3. Structural modeling research demonstrated substantial size, charge, conformation, and hydrophobicity variations between wildtype and mutant proteins. Variants positioned near conserved regions or within functional domains were anticipated to be deleterious, potentially compromising protein function and ligand interactions. Molecular docking studies verified changes in binding affinities between wildtype and mutant proteins for common ligands. The identified variations were linked to the metabolism of frequently used pharmaceuticals in Africa, such as caffeine, ketoconazole, efavirenz, carbamazepine, and artemether. Conclusions: These findings highlight the need for pharmacogenetic screening to inform personalized medicine, diminish ADRs, and enhance the clinical care of OFCs in Sub-Saharan Africa.

The differentiation cascade that converts basal keratinocytes into suprabasal layers, including periderm, depends on the activity of transcription factors. Mutations in the genes encoding many of these transcription factors, including TP63, IRF6 and GRHL3 , disrupt periderm development. Such mutations can also interfere with embryonic fusion and septation events that depend on periderm development, including palatogenesis, digit separation and the formation of temporary epithelial fusions between digits, between eyelids, and between pinnae and the scalp. ZNF750 (Zfp750 in the mouse) is a transcription factor required for keratinocyte differentiation, but whether mutations in ZNF750 contribute risk for orofacial cleft, and the role of Zfp750 in periderm development, are unknown. To address these questions we sequenced ZNF750 in 5,659 individuals including 2,125 with nonsyndromic OFC. We identify 33 rare missense variants with frequencies less than 0.1% in gnomAD. Of these, about half are predicted to be damaging with in silico tools. Collectively, these missense variants are not overtransmitted from parents to children with OFCs. Two of the variants have lower activity than the reference variant in a zebrafish embryo-based assay but no phenotype in the corresponding murine model. However, in murine embryos homozygous for a frame-shift mutation in Zfp750 ( Zfp750 ^fs ) that we generated, palatal shelves are fused but intra-oral adhesions are present, a phenotype seen in murine mutants of several bonafide OFC genes. In addition, temporary epithelial fusions are absent in Zfp750 ^fs neonates. RNA sequencing of forelimbs from Zfp750 ^fs embryos reveals decreased expression of epidermal terminal differentiation genes, and both increased and decreased expression of distinct periderm genes. Immunofluorescence shows the consistent presence of periderm proteins within the oral adhesions in Zfp750 ^fs/fs embryos. Together these studies suggest that while mutations in ZNF750 are not a major contributor to OFC risk, Zfp750 does contribute to periderm-dependent morphogenic events.

Monozygotic (MZ) twins are expected to share nearly identical genomes, yet a substantial proportion is discordant for complex diseases like nonsyndromic orofacial clefts (nsOFC). This suggests a role for postzygotic discordant genetic variations and other developmental mechanisms. In this study, we performed whole genome sequencing of two MZ twin pairs of African ancestry who were discordant for nsOFC to identify genetic variants that may contribute to phenotypic discordance. Following quality control and genotype‐level filtering, we identified 37,271 variants that were present exclusively in the affected twins. Of these, 431 variants were predicted by CADD to have deleterious effects. Among these, 66 were in protein‐coding regions, including 2 predicted protein‐altering missense variants and splice‐site variants. The remaining 365 variants were in noncoding regions including putative craniofacial enhancers. Some of these variants are rare (MAF < 0.01) and were predicted to alter transcription factor binding or disrupt local chromatin architecture within putative craniofacial enhancers located near genes with established roles in craniofacial development, including COL27A1 , MPHOSPH8 , and SPTBN1 . In addition, some common variants previously associated with noncraniofacial traits were also predicted to affect regulatory activity of putative craniofacial enhancers near craniofacial genes. This raises the possibility of pleiotropic regulatory effects that warrant further investigation. Overall, this study identified a set of candidate coding and regulatory variants in MZ twins discordant for nsOFC,providing targets for future functional investigations. We also proposed an overarching genetic mechanism for the prioritized discordant variants.

Accessory breasts denote the formation of extra breast tissue along the milk line, being more prevalent among Black and Asian populations, affecting both genders. This study aimed to determine the genetic aetiology of accessory breasts in a multiplex family, where all female siblings presented with bilateral accessory breasts. The study also ascertained secondary findings (SFs) that may impact the health of the family members. Clinical data and saliva samples were obtained from all family members. Ultrasound and histopathology confirmed the diagnosis. Whole-exome sequencing was conducted on DNA samples obtained from the saliva, with variant calling conducted utilizing Sentieon workflow. Variant classification was based on American College of Medical Genetics and Genomics guidelines. After segregation analysis, 12 candidate genes emerged. Among these, PRSS50 and FANCC emerged as top candidates, being implicated in breast diseases. However, two variants in FANCC (c.360del; p.His120GlnfsTer24 and c.355_358del; p.Ser119IlefsTer24) were selected as the most probable causal variants because of the role of this gene in familial hereditary breast and ovarian cancer syndromes. The remaining ten genes were reported as potentially accounting for co-occurring conditions segregating with accessory breasts. Reported SFs involve TTR and RYR1. In conclusion, pathogenic variants in FANCC are causal for familial accessory breasts.

Background/Objectives: Orofacial clefts (OFCs) are among the most common birth defects globally, sometimes exacerbated by adverse drug reactions (ADRs) like corticosteroids and antiepileptics. Comprehending the pharmacogenomic and pharmacogenetic elements that lead to ADRs is essential for enhancing precision medicine and clinical outcomes. This study examines rare genetic variants in drug-metabolizing and drug-transporting genes among Ghanaian and Nigerian families with a history of OFCs, intending to assess their pathogenicity and functional implications. Methods: We recruited 104 Ghanaian families and 26 Nigerian families, generating whole genome sequencing (WGS) data from 390 individuals (130 case-parent trios). DNA was isolated from saliva and buccal swab samples and estimated with a Qubit fluorometer. DNA samples underwent WGS, and WGS data analyzed through extensive bioinformatics algorithms. Variants were called and annotated using the GATK workflow. The HOPE in silico modeling tool evaluated the structural impact of genetic variants on encoded proteins, while molecular docking using PyRx examined alterations in ligand binding affinity. Results: Our study revealed pathogenic variants in vital genes associated with drug metabolism and transport, specifically CYP1A2, CYP2C18, CYP27A1, CYP2B6, SLC6A2, and ABCC3. Structural modeling research demonstrated substantial size, charge, conformation, and hydrophobicity variations between wild-type and mutant proteins. Variants positioned near conserved regions or within functional domains were anticipated to be deleterious, potentially compromising protein function and ligand interactions. Molecular docking studies verified changes in binding affinities between wildtype and mutant proteins for common ligands. The identified variations were linked to the metabolism of frequently used pharmaceuticals in Africa, such as caffeine, ketoconazole, efavirenz, carbamazepine, and artemether. Conclusions: These findings highlight the need for pharmacogenetic screening to inform personalized medicine, diminish ADRs, and enhance the clinical care of OFCs in Sub-Saharan Africa.