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OBJECTIVE: To find the different etiological factors underlying a midline diastema which will help in effective orthodontic correction by enabling the practitioner to adopt the most appropriate mechanics. METHODS: This descriptive cross-sectional study was conducted at the Department of Orthodontics, Nishtar Institute of Dentistry, Multan, from 01-08-2020 to 01-02-2021. A sample of 165 patients was analyzed according to age, gender, presenting various occlusal traits, and relevant diastema findings to assess the underlying etiology of the maxillary midline diastema. Cases with a midline diastema of >0.5 mm were documented with examination including clinical intra-oral examination and orthopantomograms and upper occlusal radiographs. Examinations were done by the same observer to reduce human error and were cross-checked by a superior to minimize the possibility of error. The data was analyzed using SPSS version 20.0. RESULTS: Dental anomalies (n=113, 68.6%) was the most frequent cause of maxillary midline diastema. Dental anomalies were observed in both females (n=77/112; 68.8%) and males (n=36/53; 67.9%). Common dental anomalies included tooth/arch size discrepancies (n=58, 51.3%), abnormal occlusal patterns (n=37; 32.7%) and missing teeth (n=18 15.9%). Other contributing factors for maxillary midline diastema observed were abnormal maxillary arch structure (n=30; 18%), physical impediments (n=18; 11%), muscular imbalances (n=3; 1.8%) and pernicious habits (n=1; 0.6%). Common causes of physical impediments were fleshy labial frenum 10/18; 55.6%) and supernumerary tooth (n=8/18; 44.4%). CONCLUSION: Maxillary midline diastema was common in both genders and was associated with multiple etiologies of which dental anomalies, abnormal maxillary arch structure and physical impediments were highly prevalent. [ABSTRACT FROM AUTHOR]

Next-generation sequencing (NGS) of exomes and genomes has accelerated the identification of genes involved in Mendelian phenotypes. However, many NGS studies fall short of identifying causal variants, with estimates for success rates as low as 25% for uncovering the pathological variant underlying disease etiology. An important reason for such failures is familial locus heterogeneity, where within a single pedigree causal variants in two or more genes underlie Mendelian trait etiology. As examples of intra- and inter-sibship familial locus heterogeneity, we present 10 consanguineous Pakistani families segregating hearing impairment due to homozygous variants in two different hearing impairment genes and a European-American pedigree in which hearing impairment is caused by four variants in three different genes. We have identified 41 additional pedigrees with syndromic and nonsyndromic hearing impairment for which a single previously reported hearing impairment gene has been identified but only segregates with the phenotype in a subset of affected pedigree members. We estimate that locus heterogeneity occurs in 15.3% (95% confidence interval: 11.9%, 19.9%) of the families in our collection. We demonstrate novel approaches to apply linkage analysis and homozygosity mapping (for autosomal recessive consanguineous pedigrees), which can be used to detect locus heterogeneity using either NGS or SNP array data. Results from linkage analysis and homozygosity mapping can also be used to group sibships or individuals most likely to be segregating the same causal variants and thereby increase the success rate of gene identification. [ABSTRACT FROM AUTHOR]

Melanin pigment helps protect our body from broad wavelength solar radiation and skin cancer. Among other pigmentation disorders in humans, albinism is reported to manifest in both syndromic and nonsyndromic forms as well as with varying inheritance patterns. Oculocutaneous albinism (OCA), an autosomal recessive nonsyndromic form of albinism, presents as partial to complete loss of melanin in the skin, hair, and iris. OCA has been known to be caused by pathogenic variants in seven different genes, so far, according to all the currently published population studies. However, the detection rate of alleles causing OCA varies from 50% to 90%. One of the significant challenges of uncovering the pathological variant underlying disease etiology is inter- and intra-familial locus heterogeneity. This problem is especially pertinent in highly inbred populations. As examples of such familial locus heterogeneity, we present nine consanguineous Pakistani families with segregating OCA due to variants in one or two different known albinism-associated genes. All of the identified variants are predicted to be pathogenic, which was corroborated by several in silico algorithms and association with diverse clinical phenotypes. We report an individual affected with OCA carries heterozygous, likely pathogenic variants in TYR and OCA2, raising the question of a possible digenic inheritance. Altogether, our study highlights the significance of exome sequencing for the complete genetic diagnosis of inbred families and provides the ramifications of potential genetic interaction and digenic inheritance of variants in the TYR and OCA2 genes. [ABSTRACT FROM AUTHOR]