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

Due to the wide range of genetic disorders that are presently known, diagnosis of a genetic disorder is widely varied and dependent of the disorder. Most genetic disorders are diagnosed at birth or during early childhood, however some, such as Huntington's disease, can escape detection until the patient is well into adulthood.

The basic aspects of a genetic disorder rests on the inheritance of genetic material. With an in depth family history, it is possible to anticipate possible disorders in children which direct medical professionals to specific tests depending on the disorder and allow parents the chance to prepare for potential lifestyle changes, anticipate the possibility of stillbirth, or contemplate termination. Prenatal diagnosis can detect the presence of characteristic abnormalities in fetal development through ultrasound, or detect the presence of characteristic substances via invasive procedures which involve inserting probes or needles into the uterus such as in amniocentesis.

Prognosis strongly depends on which subtype of disease it is. Some are deadly in infancy but most are late onset and mostly manageable.

Upington disease, also called Perthes-like hip disease, enchondromata, ecchondromata, and familial dyschondroplasia, is an extremely rare autosomal dominant malformation disorder. It has only one published source claiming its existence in three generations of one family from South Africa.

Worth syndrome is caused by a mutation in the LRP5 gene, located on human chromosome 11q13.4. The disorder is inherited in an autosomal dominant fashion. This indicates that the defective gene responsible for a disorder is located on an autosome (chromosome 11 is an autosome), and only one copy of the defective gene is sufficient to cause the disorder, when inherited from a parent who has the disorder.

Autosomal dominant porencephaly type I is rare and its prevalence and incidence are unknown. It affects males and females equally.

HDL1 is an unusual, autosomal dominant familial prion disease. Only described in one family, it is caused by an eight-octapeptide repeat insertion in the "PRNP" gene. More broadly, inherited prion diseases in general can mimic HD.

Opitz G/BBB Syndrome is a rare genetic condition caused by one of two major types of mutations: MID1 mutation on the short (p) arm of the X chromosome or a mutation of the 22q11.2 gene on the 22nd chromosome. Since it is a genetic disease, it is an inherited condition. However, there is an extremely wide variability in how the disease presents itself.

In terms of prevention, several researchers strongly suggest prenatal testing for at-risk pregnancies if a MID1 mutation has been identified in a family member. Doctors can perform a fetal sex test through chromosome analysis and then screen the DNA for any mutations causing the disease. Knowing that a child may be born with Opitz G/BBB syndrome could help physicians prepare for the child’s needs and the family prepare emotionally. Furthermore, genetic counseling for young adults that are affected, are carriers or are at risk of carrying is strongly suggested, as well (Meroni, Opitz G/BBB syndrome, 2012). Current research suggests that the cause is genetic and no known environmental risk factors have been documented. The only education for prevention suggested is genetic testing for at-risk young adults when a mutation is found or suspected in a family member.

Upington disease is inherited in an autosomal dominant manner. This means the defective gene is located on an autosome, and one copy of the defective gene is sufficient to cause the disorder, when inherited from a parent who has the disorder.

In terms of frequency, is estimated at 2 per 100,000, it has identified in different regions of the world. Some clusters of certain types of autosomal dominant cerebellar ataxia reach a prevalence of 5 per 100,000.

Oculopharyngeal muscular dystrophy (OPMD) is a rare form of muscular dystrophy with symptoms generally starting when an individual is 40 to 50 years old. It can be autosomal dominant neuromuscular disease or autosomal recessive. The most common inheritance of OPMD is autosomal dominant, which means only one copy of the mutated gene needs to be present in each cell. Children of an affected parent have a 50% chance of inheriting the mutant gene.

Autosomal dominant inheritance is the most common form of inheritance. Less commonly, OPMD can be inherited in an autosomal recessive pattern, which means that two copies of the mutated gene need to be present in each cell, both parents need to be carriers of the mutated gene, and usually show no signs or symptoms. The PABPN1 mutation contains a GCG trinucleotide repeat at the 5' end of the coding region, and expansion of this repeat which then leads to autosomal dominant oculopharyngeal muscular dystrophy (OPMD) disease.

Worth syndrome, also known as benign form of Worth hyperostosis corticalis generalisata with torus platinus, autosomal dominant osteosclerosis, autosomal dominant endosteal hyperostosis or Worth disease, is a rare autosomal dominant congenital disorder that is caused by a mutation in the LRP5 gene. It is characterized by increased bone density and benign bony structures on the palate.

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal dominant disorder characterized by cleft palate and congenital contractures of the hands and feet.

Other neurogenetic disorders can cause an HD-like or HD phenocopy syndrome but are not solely defined as HDL syndromes. The commonest is spinocerebellar ataxia type 17 (SCA-17), occasionally called HDL-4. Others include mutations in "C9orf72", spinocerebellar ataxias type 1 and 3, neuroacanthocytosis, dentatorubral-pallidoluysian atrophy (DRPLA), brain iron accumulation disorders, Wilson's disease, benign hereditary chorea, Friedreich's ataxia, mitochondrial disease.

A Huntington's disease-like presentation may also be caused by acquired causes.

The genetics of congenital muscular dystrophy are autosomal recessive which means two copies of an abnormal gene must be present

for the disease or trait to happen. In the case of collagen VI-deficient, it is autosomal dominant, which means a child could inherit the disease from only one copy of a gene present in only one parent.

The prevalence for congenital muscular dystrophy seems to be between 2.6-4.5 in 10,000 according to Reed, 2009. MDCIA, for example is due to a mutation in the LAMA-2 gene and is involved with the 6q2 chromosome.

Acro–dermato–ungual–lacrimal–tooth (ADULT) syndrome is a rare genetic disease. ADULT syndrome is an autosomal dominant form of ectodermal dysplasia, a group of disorders that affects the hair, teeth, nails, sweat glands, and extremities. The syndrome arises from a mutation in the TP63 gene. This disease was previously thought to be a form of ectrodactyly–ectodermal dysplasia–cleft syndrome (EEC), but was classified as a different disease in 1993 by Propping and Zerres.

While some reports suggest Gordon syndrome may be inherited in an X-linked dominant manner, most agree that it is inherited in an autosomal dominant manner with reduced expressivity and incomplete penetrance in females.

In autosomal dominant inheritance, having only one mutated copy of the disease-causing gene in each cell is sufficient to cause signs and symptoms of the condition. When an individual with an autosomal dominant condition has children, each child has a 50% (1 in 2) risk to inherit the mutated copy of the gene.

If a condition shows variable or reduced expressivity, it means that there can be a range in the nature and severity of signs and symptoms among affected individuals. Incomplete penetrance means that a portion of the individuals who carry the mutated copy of the disease-causing gene will not have any features of the condition.

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.

The disease is found across 5 continents (30 countries) and is frequently seen in French Canadians, with a prevalence 1:1000. OPMD affects males and females equally, and affected individuals have been found in Europe (France), Jewish Ashkenazi, and Spanish Americans.

There is currently no cure for the disease but treatments to help the symptoms are available.

Ramos-Arroyo syndrome is marked by corneal anesthesia, absence of the peripapillary choriocapillaris and retinal pigment epithelium, bilateral sensorineural hearing loss, unusual facial appearance, persistent ductus arteriosus, Hirschsprung disease, and moderate intellectual disability. It appears to be a distinct autosomal dominant syndrome with variable expressivity.

As of 2008 this syndrome has only been reported in five individuals within three generations of the same family; two young children, their mother, their uncle and their maternal grandmother. This most recent generation to be diagnosed with Ramos-Arroyo syndrome supports the hypothesis that this disease is a distinct autosomal

dominant disorder. If this syndrome could be identified in other families it may help to discriminate the gene responsible.

Steatocystoma multiplex, also known as epidermal polycystic disease and sebocystomatosis, is a benign, autosomal dominant congenital condition resulting in multiple cysts on a person's body. Steatocystoma simplex is the solitary counterpart to steatocystoma multiplex.

Since the symptoms caused by this disease are present at birth, there is no “cure.” The best cure that scientists are researching is awareness and genetic testing to determine risk factors and increase knowledgeable family planning. Prevention is the only option at this point in time for a cure.

This disease is more common in women and an association with the gene FLT4 has been described. FLT4 codes for VEGFR-3, which is implicated in development of the lymphatic system.

Milroy's disease is also known as primary or hereditary lymphedema type 1A or early onset lymphedema.

It is a very rare disease with only about 200 cases reported in the medical literature. Milroy's disease is an autosomal dominant condition caused by a mutation in the FLT4 gene which encodes of the vascular endothelial growth factor receptor 3 (VEGFR-3) gene located on the long arm (q) on chromosome 5 (5q35.3).

In contrast to Milroy's disease (early onset lymphedema type 1A,) which typically has its onset of swelling and edema at birth or during early infancy, hereditary lymphedema type II, known as Meige disease, has its onset around the time of puberty. Meige disease is also an autosomal dominant disease. It has been linked to a mutations in the ‘forkhead’ family transcription factor (FOXC2) gene located on the long arm of chromosome 16 (16q24.3). About 2000 cases have been identified. A third type of hereditary lymphedema, that has an onset after the age of 35 is known as lymph-edema tarda.

Central core disease (CCD), also known as central core myopathy, is an autosomal dominant congenital myopathy (inborn muscle disorder). It was first described by Shy and Magee in 1956. It is characterized by the appearance of the myofibril under the microscope.