Background Chromosome 18 has 337 genes and the lowest gene density of all the human chromosomes

Chromosome 18 has 337 genes and the lowest gene density of all the human chromosomes. There are 4.4 genes per Megabase and it contains several gene deserts which make up 38% of the whole chromosome. Overall, chromosome 18 embodies 2.7% of the entire human genome (Peron & Carey, 2014). Although chromosome 18 contains few genes, it still produces a variety of abnormalities when these genes are interfered with. Two different aberrations of this chromosome include trisomy 18 and distal 18q deletion.
Trisomy 18, also known as Edwards syndrome, is a common autosomal trisomy. It is the second most common autosomal trisomy in live births, following trisomy 21 (Chen et al., 2005). After multiple populations studies conducted world-wide, the prevalence of live births with trisomy 18 is estimated to range from 1 in 3600 to 1 in 10,000, with the best estimated prevalence to be 1 in 6000 live births (Cereda, 2012). The risk of having a trisomy 18 offspring is increased as maternal age increases (Genetics Home Reference, 2012). Most diagnoses of trisomy 18 is done through the use of prenatal screening based on maternal age or maternal serum marker screening and amniocentesis. Therefore, the overall prevalence of trisomy 18 is expected to be higher than the live birth prevalence. Recent studies have shown that the overall prevalence for trisomy 18 has increased over the last 20 years due to the increase in maternal age, although there has been a decrease in live birth due to the increased use of prenatal diagnosis and the high rate of termination after diagnosis (Cereda, 2012). Infants with trisomy 18, if they make it full term, often die within their first month, although 5 to 10 percent live past their first year (Genetics Home Reference, 2012).
Distal 18q deletion syndrome, also known as De Grouchy syndrome, occurs when the end part of the long (q) arm of chromosome 18 is missing (Genetics Home Reference, 2017). Deletions of the long arm of chromosome 18 are one of the more common chromosome abnormalities, occurring in 1 in 40,000 live births (Genetics Home Reference, 2017; Schaub, Hale, Rose, Leach, & Cody, 2005). Distal 18q deletion syndrome has a highly variable phenotype due to a lack of uniformity in the genotype (Cody et al., 2015). The size of the deletion and the location of the deletion can be different in each 18q deletion. Distal 18q deletions can occur anywhere between 18q21 and the terminal end and the severity of the phenotype is directly related to the size and location of the deletion (Genetics Home Reference, 2017; Schaub et al., 2005). Distal 18q deletion syndrome (terminal deletion) occurs more frequently than proximal 18q deletion syndrome (interstitial deletion) but quite often these two syndromes are researched and analysed together in order to gain better understanding in the differing clinical features with regards to the deletions seen in each disorder (Cody, Heard, et al., 2009).
Clinical characteristics of trisomy 18
Trisomy 18 is associated with many abnormalities that affect much of the body with the possibility that some of these abnormalities can be identified in prenatal testing. Trisomy 18 can be indicated by soft sonographic markers seen in late first to early second trimester. These markers include increase nuchal translucency thickness and the absence or hypoplasia of the nasal bone. Other structural anomalies that can be detected in first trimester sonography include omphalocele, abnormal posturing of hands, megacystis, heart abnormalities and intrauterine growth retardation (IUGR) (Cereda, 2012). As an infant the clinical features of trisomy 18 include low birth weight; small, abnormally shaped head; a small jaw and mouth; clenched fist with overlapping fingers; small fingernails; underdeveloped thumbs; short sternum and club feet (Cereda, 2012; Genetics Home Reference, 2012). Trisomy 18 individuals can also have psychomotor and cognitive developmental delay and craniofacial features which can include dolichocephaly, short palpebral fissures, micrognathia, external anomalies of the ears and extra skin at the back of their necks (Cereda, 2012). These features are the typical features seen in children/infants with trisomy 18 although each phenotype can be different and may contain a different combination of anomalies.
Genetic mechanisms of trisomy 18
Trisomy 18 occurs due to an extra whole chromosome 18 is present in every cell. Most studies suggest that nondisjunction is the cause of the extra chromosome. With the introduction of DNA polymorphism analysis, parental origin and non-disjunction of trisomy 18 could be studied. Studies show that in the majority of cases the extra chromosome was of maternal origin, with approximately 50% of the nondisjunction errors occurring in meiosis II. This is different to most other trisomies where the majority of errors occur in meiosis I. Only in a minority of cases is the extra chromosome paternally derived, where the error is due to postzygotic error (Cereda, 2012). Other studies have found similar results where around 90% of cases the extra chromosome was of maternal origin, with approximately 60% due to meiosis II errors, between 30-35% were meiosis I errors and between 4-8% were a maternal post zygotic mitotic error or non-crossover meiosis II error (Chen et al., 2005; Nicolaidis, 1998). The exact mechanisms and reasons behind how and why these errors occurs is not well understood, although advance maternal age has been linked to an increased frequency of nondisjunction errors.
Clinical characteristics of distal 18q deletion syndrome
Due to the phenotype of distal 18q deletion syndrome being highly variable, it is difficult to give defined clinical characteristics. Common characteristics seen in this deletion can include cognitive impairment, short stature, hypotonia, ear canal abnormalities, foot deformities (club foot or rocker-bottom feet), genital abnormalities and delayed myelination. Other features that are quite common include proximally placed thumbs, kidney malformations and growth hormone deficiency (Cody, Heard, et al., 2009). Microcephaly, eye movement disorders and vision problems, cleft palate, hypothyroidism, congenital heart defects, kidney problems and skin problems are also seen in this deletion. Some individuals have mild facial differences including deep-set eyes, midface hypoplasia, wide mouth and prominent ears. The cognitive impairment seen can include delayed development, learning disabilities, intellectual disabilities, seizures, hyperactivity, anxiety, depression and features of autism spectrum disorder (Genetics Home Reference, 2017). As the phenotype is highly variable and depends on the size and location of the deletion, studies have been conducted to attempt to discover which genes are responsible for certain clinical features.
Genetic mechanisms of distal 18q deletion syndrome
Distal 18q deletion syndrome is thought to be an autosomal dominant condition, only requiring one copy of the genes to be deleted to cause the clinical features. In some cases, distal 18q deletion syndrome can be inherited from a mildly affected parent. High variability is seen in phenotypes even in families, so the child may have a more severe phenotype than the parent has. It can also be inherited from a parent who carries a balanced translocation, which can be passed on to the offspring in an unbalanced form. This occurs when the derivative chromosome 18 is inherited by the child, causing the child to have a deletion in chromosome 18. Inheriting an unbalanced form from a parental balanced translocation can also lead to the derivative chromosome having extra genes from another chromosome. This causes partial trisomy for part of another chromosome, which can affect the phenotype seen. Most cases of distal 18q deletion syndrome are de novo, usually resulting from a random event occurring during the formation of gametes or in early fetal development (Genetics Home Reference, 2017)
Genotype/phenotype correlations
Chromosome 18 abnormalities, such as trisomy 18 and distal 18q deletion, can produced highly variable phenotypes (Linnankivi et al., 2006). Although advancements in molecular technology, such as microarray, have allowed scientists to detect smaller copy number variants, linking genotype to phenotype is still a major challenge. Feenstra et al, in 2007, refined the critical regions of some common clinical features of people with 18q deletions. This included the critical regions for microcephaly (18q21.33), short stature (18q21.1-q21.33 and 18q22.3-q23), white matter disorders and delayed myelination (18q22.3-q23), growth hormone insufficiency (18q22.3-q23) and congenital aural atresia (18q22.3) (Feenstra et al., 2007).
In a 2009 study by Cody et al, a gene dosage map was produced by analysing data from scientific literature and online databases. The study identified gene dosage status of known genes and related this to critical regions for specific phenotypes (Cody, Carter, Sebold, Heard, & Hale, 2009). 253 genes were assessed for dosage sensitivity and divided into 5 categories, haplolethal (dosage critical), haploinsufficient (dosage sensitive), conditional haploinsufficient (conditional dosage sensitive), haplosufficient (dosage insensitive) and unknown. The status of most genes was found to be unknown, with the majority of the known genes to be haplosufficient (Cody, Carter, et al., 2009). This leads to the hypothesis that relatively few genes are responsible for the major phenotypes seen in 18q deletions (Cody, Heard, et al., 2009).
Others studies have been completed after the gene dosage map was published, to increase the knowledge of the genes on chromosome 18 and the affect they have on the phenotype. Most studies done in an effort to make a connection between genotype and phenotype, analyse a large group of people with deletions in a particular area. This data is used in an attempt to match the overlapping gene deletions to a particular phenotype seen in the patients. In 2009, Cody et al, found the critical regions and penetrance for four phenotypic features of distal 18q deletions. The study found that kidney malformation had a critical region of 3.21Mb and had a penetrance of 25%, dysmyelination had a critical region of 1.62Mb and a penetrance of 100%, growth hormone response failure was also 1.62Mb with a penetrance of 90% and aural atresia had a critical region of 2.3Mb with a penetrance of 78%. This study concluded by stating the next step was to identify specific genes responsible for various phenotypic traits (Cody, Heard, et al., 2009).
A study by Cody et al in 2015, analysed 350 people with 18q deletions, which is one of the largest cohorts reported in literature for this type of study. From this cohort they found that the location and size of the deletions found varied greatly and that each person had a unique region of hemizygosity. This 2015 study used the same 5 categories to describe the genes on chromosome 18 as the 2009 study and it was found that 15 of the 196 genes on 18q were haploinsufficient. It was also discovered that there were two regions on 18q that were not found to be hemizygous in anyone, leading to the theory that these regions could be haplolethal. One of these regions was adjacent to the centromere and the other at 18q21.1, effectively splitting 18q into two regions, proximal 18q and distal 18q (Cody et al., 2015).
Focusing on the distal 18q region, 18q21.1-18qter, 8 genes have been categorised as haplosufficient when hemizygous. These genes and the corresponding phenotype can be viewed in table 1. Deletions in the TCF4 gene were found to cause Pitt-Hopkins syndrome, which is a condition that causes sever intellectual disability and breathing problems (Cody et al., 2015; Genetics Home Reference, 2011).
Table 1: Phenotype Characteristics of distal 18q deletions, Gene and Chromosome Locations

Gene and gene locations of phenotype characteristics of distal 18q deletion (Cody et al., 2015).

In regards to trisomy 18, most studies are done on partial trisomy of 18p or 18q in order to work out what genes may be responsible for certain clinical features. An article written by Peron and Carey in 2014, reviewed the scientific literature for trisomy 18 phenotypes and genotypes. In the review of partial trisomy of 18p, it was found that it was generally accepted that the short arm of chromosome 18 did not contain genes that contributed to the trisomy 18 phenotype. A mild phenotype is seen in patients with duplications in 18p, with some patients displaying atrial septum defects, club feet, mild psychomotor impairment, mild cognitive impairment, anorectal malformation, patent ductus arteriosus and mild facial abnormalities (Peron & Carey, 2014).
More studies have been conducted on the partial trisomy of 18q than for partial trisomy of 18p. Peron and Carey proposed a phenotypic map of chromosome 18 using the literature in an attempt to establish a better understanding of the phenotype/genotype correlation. This was completed by analysing the most common clinical features of trisomy 18 and attempting to find a critical region that is responsible for each phenotypic feature (Peron & Carey, 2014). Although most patients with a partial trisomy of chromosome 18 had structural heart defects, the study was not able to find a unique common duplicated region, instead narrowing it down to three possible regions.
Table 2: Phenotype Characteristics of trisomy 18 and Critical Region Location
Gene and gene locations of phenotype characteristics of trisomy 18 (Peron & Carey, 2014).

The study also analysed the characteristic facial and physical features of trisomy 18, but could not find a unique duplication region shared but multiple patients. It was noticed that the region 18q21.2 was frequently involved in duplication of affected individuals. All that was able to be concluded was that the genes responsible for facial characteristics are found on the q arm of chromosome 18 (Peron & Carey, 2014).
Determining specific genes or critical regions for phenotypic characteristics seen in either trisomy 18 or distal 18q deletion is a difficult task. In order to make a link between gene and phenotype, a large amount of analysis needs to occur to minimise the critical region and hopefully pinpoint the gene or genes responsible. Each study that is undertaken aids to shorten the critical regions and give direction to future studies.