Clinical AreaOral and maxillofacial surgery

Here you will find the disease-related gene panels available for the clinical area specified above.

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Molecular genetic diagnostics are also prone to clarify the hereditary causes of diseases from the spectrum of oral and maxillofacial surgery (MKG). The aim here is to detect deviations from the reference genome ("wild type") and then, if necessary, to differentiate between neutral genetic variants and pathogenic mutations that are important for physiological development and proper functioning. The heredity patterns of MKG diseases are the basis of genetic counselling for patients, persons at risk and affected families. Over the past 30 years, numerous genes have been characterized whose changes cause the broad spectrum of MKG diseases or contribute to the development of these diseases. Current research results have a direct impact on the diagnostic procedure in the laboratory and genetic counselling. For example, mutations in independent genes on different chromosomes can cause clinically indistinguishable, hereditary diseases ("locus heterogeneity"; see craniosynostoses). On the other hand, different mutations in one and the same gene can lead to clinically apparently separated disease entities ("allelic heterogeneity"; TP63 gene mutations cause orofacial clefts [type 8] or e.g. ADULT [Acro-Dermato-Ungual-Lacrimal-Tooth] syndrome).

Formal genetically and etiologically, the following groups of MKG diseases can be distinguished:

• monogenic diseases (autosomal or X-chromosomal inheritance)
• digenic diseases, which only are manifested when mutations are simultaneously present in heterozygous state in two different genes. Physiologically the two normal gene products together form functional heterodimers. Digenic inheritance concerns ~3% of hereditary diseases in addition to the classic autosomal and X-linked diseases.
• mitochondrial diseases (maternal or autosomal inheritance)
• multifactorial diseases (interaction of several to many genes plus environmental factors)

Congenital malformations in the MKG area often appear sporadically - is there a genetic (co-)cause? A great many inherited MKG disorders are demonstrably based on genetic changes and lead to disorders with altered MKG structures. DNA diagnostics therefore often involves a step-by-step procedure in which the most frequent mutations are first examined before the very rare genetic causes are also identified in parallel approaches using expanded and cost-intensive panel procedures. Mutations found and all variants with unclear significance (VUS) are verified by DNA sequence analysis using the Sanger technique. In the following, only four more frequent disease groups are listed in more detail.

Lip-jaw-palate (LKG) clefts are known to be the most common congenital malformations, accounting for ~15% of all cases. In Central Europe, one in 650 newborns is affected - with boys slightly more frequently than girls. Nowadays, the diagnosis is usually already made by ultrasound during the pregnancy. The vast majority of LKG clefts are multifactorial, involving several genetic variants and still little known environmental factors. Therefore, the genetic causes of LKG clefts a priori can only be determined in larger research projects. However, the latter work has also made it possible to diagnose (very) rare causes of clefting, with up to 150 and more monogenic defects becoming accessible to direct DNA diagnostics. For the latter subtypes of this spectrum, the inheritance patterns are precisely known and the genetic defects can be detected directly. If the clinical diagnosis remains less specific, even very large gene panels are available for differential diagnosis.

Even more extensive and complex facial malformations include the differential diagnosis of frontonasal dysplasia, facial clefts of different Tessier types and the Opitz G/BBB syndromes (with different inheritance modes), which are associated with laryngo-tracheo-esophageal defects and hypospadias in addition to variably pronounced facial cleft or hypertelorism. The amedes db also harbors gene panels for this spectrum of disorders.

Rasopathies include some rare related syndromes (Costello, LEOPARD and Cardio-Fazio-Cutaneous [CFC] syndrome), the more common Noonan syndrome as well as neurofibromatosis type 1 (NF1) and similar disorders (Legius, NF1-Noonan syndrome). Common to all rasopathies are genetic changes that cause a constitutional dysregulation of the RAS-MAPK pathway. This results in a typical pattern of congenital malformations and developmental disorders of variable severity. Clinical features include cardiac abnormalities, reduced growth and particularly craniofacial dysmorphia. Skin and nervous system develop from the ectoderm. Neurocutaneous syndromes are by definition characterized by combinations of symptoms with different skin findings involving the peripheral and/or central nervous system. A more frequent entity from these rare monogenic diseases is the autosomal dominantly inherited NF1, the treatment of which also belongs to the MKG spectrum - like surgical interventions for other rare hereditary tumors and vascular malformations of the face and oral cavity. Due to the genetic heterogeneity of these clinical pictures, increasingly comprehensive gene panels are used for differential diagnosis by DNA sequence analysis after initial clarification of the most common types.

In uncomplicated synostoses, only one single cranial suture is closed prematurely, which leads to growth inhibition perpendicular to the suture as well as the formation of one of the typical head shapes depending on the cranial suture. Distinction is necessary between Scaphocephaly/dolichocephaly (sagittal suture synostosis), trigonocephaly (frontal suture synostosis), anterior plagiocephaly (coronal suture synostosis), posterior plagiocephaly (lambda suture synostosis) as well as multiple and syndromal craniosynostoses. The genetic heterogeneity of craniosynostoses is taken into account by a basic panel with more than a dozen genes and an extended panel with almost 50 genes.