Genetic disorders may also be complex, multifactorial, or polygenic, meaning they are likely associated with the effects of multiple genes in combination with lifestyles and environmental factors. Multifactorial disorders include heart disease and diabetes. Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a person’s risk of inheriting or passing on these disorders. Complex disorders are also difficult to study and treat, because the specific factors that cause most of these disorders have not yet been identified. Studies which aim to identify the cause of complex disorders can use several methodological approaches to determine genotype-phenotype associations. One method, the genotype-first approach, starts by identifying genetic variants within patients and then determining the associated clinical manifestations. This is opposed to the more traditional phenotype-first approach, and may identify causal factors that have previously been obscured by clinical heterogeneity, penetrance, and expressivity.

On a pedigree, polygenic diseases do tend to "run in families", but the inheritance does not fit simple patterns as with Mendelian diseases. But this does not mean that the genes cannot eventually be located and studied. There is also a strong environmental component to many of them (e.g., blood pressure).

- asthma

- autoimmune diseases such as multiple sclerosis

- cancers

- ciliopathies

- cleft palate

- diabetes

- heart disease

- hypertension

- inflammatory bowel disease

- intellectual disability

- mood disorder

- obesity

- refractive error

- infertility

The overall prognosis is excellent in most cases. Most children with Adams–Oliver syndrome can likely expect to have a normal life span. However, individuals with more severe scalp and cranial defects may experience complications such as hemorrhage and meningitis, leading to long-term disability.

Patients with CHH usually suffer from cellular immunodeficiency. In the study of 108 Finnish patients with CHH there was detected mild to moderate form of lymphopenia, decreased delayed type of hypersensitivity and impaired responses to phytohaemagglutinin. This leads to susceptibility to and, in some more severe cases, mortality from infections early in childhood. There has also been detected combined immunodeficiency in some patients

Patients with CHH often have increased predispositions to malignancies.

A genetic disorder is a genetic problem caused by one or more abnormalities in the genome, especially a condition that is present from birth (congenital). Most genetic disorders are quite rare and affect one person in every several thousands or millions.

Genetic disorders may be hereditary, passed down from the parents' genes. In other genetic disorders, defects may be caused by new mutations or changes to the DNA. In such cases, the defect will only be passed down if it occurs in the germ line. The same disease, such as some forms of cancer, may be caused by an inherited genetic condition in some people, by new mutations in other people, and mainly by environmental causes in other people. Whether, when and to what extent a person with the genetic defect or abnormality will actually suffer from the disease is almost always affected by the environmental factors and events in the person's development.

Some types of recessive gene disorders confer an advantage in certain environments when only one copy of the gene is present.

AOS is a rare genetic disorder and the annual incidence or overall prevalence of AOS is unknown. Approximately 100 individuals with this disorder have been reported in the medical literature.

There have been 30 cases of Marden-Walker Syndrome reported since 1966. The first case of this was in 1966 a female infant was diagnosed with blepharophimosis, joint contractures, arachnodactyly and growth development delay. She ended up passing at 3 months due to pneumonia.

The severity and prognosis vary with the type of mutation involved.

SUCLA2 and RRM2B related forms result in deformities to the brain. A 2007 study based on 12 cases from the Faroe Islands (where there is a relatively high incidence due to a founder effect) suggested that the outcome is often poor with early lethality. More recent studies (2015) with 50 people with SUCLA2 mutations, with range of 16 different mutations, show a high variability in outcomes with a number of people surviving into adulthood (median survival was 20 years. There is significant evidence (p = 0.020) that people with missense mutations have longer survival rates, which might mean that some of the resulting protein has some residual enzyme activity.

RRM2B mutations have been reported in 16 infants with severe encephalomyopathic MDS that is associated with early-onset (neonatal or infantile), multi-organ presentation, and mortality during infancy.

A low socioeconomic status in a deprived neighborhood may include exposure to “environmental stressors and risk factors.” Socioeconomic inequalities are commonly measured by the Cartairs-Morris score, Index of Multiple Deprivation, Townsend deprivation index, and the Jarman score. The Jarman score, for example, considers “unemployment, overcrowding, single parents, under-fives, elderly living alone, ethnicity, low social class and residential mobility.” In Vos’ meta-analysis these indices are used to view the effect of low SES neighborhoods on maternal health. In the meta-analysis, data from individual studies were collected from 1985 up until 2008. Vos concludes that a correlation exists between prenatal adversities and deprived neighborhoods. Other studies have shown that low SES is closely associated with the development of the fetus in utero and growth retardation. Studies also suggest that children born in low SES families are “likely to be born prematurely, at low birth weight, or with asphyxia, a birth defect, a disability, fetal alcohol syndrome, or AIDS.” Bradley and Corwyn also suggest that congenital disorders arise from the mother’s lack of nutrition, a poor lifestyle, maternal substance abuse and “living in a neighborhood that contains hazards affecting fetal development (toxic waste dumps).” In a meta-analysis that viewed how inequalities influenced maternal health, it was suggested that deprived neighborhoods often promoted behaviors such as smoking, drug and alcohol use. After controlling for socioeconomic factors and ethnicity, several individual studies demonstrated an association with outcomes such as perinatal mortality and preterm birth.

The TK2 related myopathic form results in muscle weakness, rapidly progresses, leading to respiratory failure and death within a few years of onset. The most common cause of death is pulmonary infection. Only a few people have survived to late childhood and adolescence.

Marden–Walker syndrome (MWS) is a rare autosomal recessive congenital disorder. It is characterized by blepharophimosis, microcephaly, micrognathia, multiple joint contractures, arachnodactyly, camptodactyly, kyphoscoliosis, and delayed motor development and is often associated with cystic dysplastic kidneys, dextrocardia, Dandy-Walker malformation, and agenesis of corpus callosum".

Trisomy 8 mosaicism affects wide areas of chromosome 8 containing many genes, and can thus be associated with a range of symptoms.

- Mosaic trisomy 8 has been reported in rare cases of Rothmund-Thomson syndrome, a genetic disorder associated with the DNA helicase RECQL4 on chromosome 8q24.3. The syndrome is "characterized by skin atrophy, telangiectasia, hyper- and hypopigmentation, congenital skeletal abnormalities, short stature, premature aging, and increased risk of malignant disease".

- Some individuals trisomic for chromosome 8 were deficient in production of coagulation factor VII due to a factor 7 regulation gene (F7R) mapped to 8p23.3-p23.1.

- Trisomy and other rearrangements of chromosome 8 have also been found in tricho–rhino–phalangeal syndrome.

- Small regions of chromosome 8 trisomy and monosomy are also created by recombinant chromosome 8 syndrome (San Luis Valley syndrome), causing anomalies associated with tetralogy of Fallot, which results from recombination between a typical chromosome 8 and one carrying a parental paracentric inversion.

- Trisomy is also found in some cases of chronic myeloid leukaemia, potentially as a result of karyotypic instability caused by the fusion gene.

Different genetic causes and types of Leigh syndrome have different prognoses, though all are poor. The most severe forms of the disease, caused by a full deficiency in one of the affected proteins, cause death at a few years of age. If the deficiency is not complete, the prognosis is somewhat better and an affected child is expected to survive 6–7 years, and in rare cases, to their teenage years.

The effects of paternal age on offspring are not yet well understood and are studied far less extensively than the effects of maternal age. Fathers contribute proportionally more DNA mutations to their offspring via their germ cells than the mother, with the paternal age governing how many mutations are passed on. This is because, as humans age, male germ cells acquire mutations at a much faster rate than female germ cells.

Around a 5% increase in the incidence of ventricular septal defects, atrial septal defects, and patent ductus arteriosus in offspring has been found to be correlated with advanced paternal age. Advanced paternal age has also been linked to increased risk of achondroplasia and Apert syndrome. Offspring born to fathers under the age of 20 show increased risk of being affected by patent ductus arteriosus, ventricular septal defects, and the tetralogy of Fallot. It is hypothesized that this may be due to environmental exposures or lifestyle choices.

Research has found that there is a correlation between advanced paternal age and risk of birth defects such as limb anomalies, syndromes involving multiple systems, and Down's syndrome. Recent studies have concluded that 5-9% of Down's syndrome cases are due to paternal effects, but these findings are controversial.

There is concrete evidence that advanced paternal age is associated with the increased likelihood that a mother will suffer from a miscarriage or that fetal death will occur.

Cartilage–hair hypoplasia (CHH), also known as McKusick type metaphyseal chondrodysplasia, is a rare genetic disorder. It is a highly pleiotropic disorder that clinically manifests by form of short-limbed dwarfism due to skeletal dysplasia, variable level of immunodeficiency and predisposition to malignancies in some cases. It was first reported in 1965 by McKusick et al. Actor Verne Troyer is affected with this form of dwarfism, as was actor Billy Barty, who was renowned for saying "The name of my condition is Cartilage Hair Syndrome Hypoplasia, but you can just call me Billy."

Genetic models of SLOS are created by knocking out the "DHCR7" gene. One study used homologous recombination to disrupt "DCHR7" in mouse embryonic stem cells. Similar to what is found in humans, heterozygous mice (having only one mutated allele) were phentoypically normal, and were crossed to produce pups (young mice) homozygous for the mutated allele. Although these pups died within the first day of life due to their inability to feed, they showed characteristics similar to humans with SLOS. They had decreased levels of cholesterol, increased levels of 7- and 8DHC, showed less growth and smaller birth weights, had craniofacial malformations, and less movement. Many also had a cleft palate, and decreased neuronal responses to glutamate. Overall however, the pups had fewer dysmorphic features than human patients with SLOS; they did not present limb, renal, adrenal or central nervous system malformations. This is explained by the fact that in rodents, maternal cholesterol can cross the placenta, and actually appears to be essential for the development of the fetus. In humans, very little maternal cholesterol is transferred to the fetus. In sum, the genetic mouse model is helpful to explain the neuropathophysiology of SLOS.

About 1 in 4,000 children in the United States will develop mitochondrial disease by the age of 10 years. Up to 4,000 children per year in the US are born with a type of mitochondrial disease. Because mitochondrial disorders contain many variations and subsets, some particular mitochondrial disorders are very rare.

The average number of births per year among women at risk for transmitting mtDNA disease is estimated to approximately 150 in the United Kingdom and 800 in the United States.

Kearns–Sayre syndrome occurs spontaneously in the majority of cases. In some cases it has been shown to be inherited through mitochondrial, autosomal dominant, or autosomal recessive inheritance. There is no predilection for race or sex, and there are no known risk factors. As of 1992 there were only 226 cases reported in published literature.

Given that SLOS is caused by a mutation in an enzyme involved in cholesterol synthesis, the resulting biochemical characteristics may be predictable. Most patients have lowered plasma cholesterol levels (hypocholesterolemia). However, approximately 10% may show normal cholesterol levels, and decreased concentrations of cholesterol are not solely indicative of SLOS. Increased levels of cholesterol precursors are also common in SLOS. In particular, elevated levels of 7-dehydrocholesterol are fairly specific to SLOS.

Neuropathy, ataxia, and retinitis pigmentosa, also known as NARP syndrome, is a rare disease with mitochondrial inheritance that causes a variety of signs and symptoms chiefly affecting the nervous system Beginning in childhood or early adulthood, most people with NARP experience numbness, tingling, or pain in the arms and legs (sensory neuropathy); muscle weakness; and problems with balance and coordination (ataxia). Many affected individuals also have vision loss caused by changes in the light-sensitive tissue that lines the back of the eye (the retina). In some cases, the vision loss results from a condition called retinitis pigmentosa. This eye disease causes the light-sensing cells of the retina gradually to deteriorate.

Miller syndrome is a genetic condition also known as the Genee–Wiedemann syndrome, Wildervanck–Smith syndrome, or postaxial acrofacial dystosis. The incidence of this condition is not known, but it is considered extremely rare. It is due to a mutation in the DHODH gene. Nothing is known of its pathogenesis.

Trisomy 8, also known as Warkany syndrome 2, is a human chromosomal disorder caused by having three copies (trisomy) of chromosome 8. It can appear with or without mosaicism.

The differential diagnosis includes Treacher Collins syndrome, Nager acrofacial dysostosis (preaxial cranial dysostosis). Other types of axial cranial dysostosis included the Kelly, Reynolds, Arens (Tel Aviv), Rodríguez (Madrid), Richieri-Costa and Patterson-Stevenson-Fontaine forms.

Malpuech facial clefting syndrome, also called Malpuech syndrome or Gypsy type facial clefting syndrome, is a rare congenital syndrome. It is characterized by facial clefting (any type of cleft in the bones and tissues of the face, including a cleft lip and palate), a appendage (a "human tail"), growth deficiency, intellectual and developmental disability, and abnormalities of the renal system (kidneys) and the male genitalia. Abnormalities of the heart, and other skeletal malformations may also be present. The syndrome was initially described by Guilliaume Malpuech and associates in 1983. It is thought to be genetically related to Juberg-Hayward syndrome. Malpuech syndrome has also been considered as part of a spectrum of congenital genetic disorders associated with similar facial, urogenital and skeletal anomalies. Termed "3MC syndrome", this proposed spectrum includes Malpuech, Michels and Mingarelli-Carnevale (OSA) syndromes. Mutations in the "COLLEC11" and "MASP1" genes are believed to be a cause of these syndromes. The incidence of Malpuech syndrome is unknown. The pattern of inheritance is autosomal recessive, which means a defective (mutated) gene associated with the syndrome is located on an autosome, and the syndrome occurs when two copies of this defective gene are inherited.

Currently there is no curative treatment for KSS. Because it is a rare condition, there are only case reports of treatments with very little data to support their effectiveness. Several promising discoveries have been reported which may support the discovery of new treatments with further research. Satellite cells are responsible for muscle fiber regeneration. It has been noted that mutant mtDNA is rare or undetectable in satellite cells cultured from patients with KSS. Shoubridge et al. (1997) asked the question whether wildtype mtDNA could be restored to muscle tissue by encouraging muscle regeneration. In the forementioned study, regenerating muscle fibers were sampled at the original biopsy site, and it was found that they were essentially homoplasmic for wildtype mtDNA. Perhaps with future techniques of promoting muscle cell regeneration and satellite cell proliferation, functional status in KSS patients could be greatly improved.

One study described a patient with KSS who had reduced serum levels of coenzyme Q10. Administration of 60–120 mg of Coenzyme Q10 for 3 months resulted in normalization of lactate and pyruvate levels, improvement of previously diagnosed first degree AV block, and improvement of ocular movements.

A screening ECG is recommended in all patients presenting with CPEO. In KSS, implantation of pacemaker is advised following the development of significant conduction disease, even in asymptomatic patients.

Screening for endocrinologic disorders should be performed, including measuring serum glucose levels, thyroid function tests, calcium and magnesium levels, and serum electrolyte levels. Hyperaldosteronism is seen in 3% of KSS patients.