Common Genetic Syndromes

The large number of known genetic disorders might be intimidating for a resident. Fortunately, when starting a genetics rotation, you only need to know about a few of the most common disorders and begin thinking about broad categories of genetic disease—rather than knowing every condition.

Some of the most common diagnoses made by geneticists are listed below, grouped into categories by mutation type, organ system involved, and pathophysiology:

Common Genetic Syndromes

Category	Disorder	Characteristic Features*
Aneuploidies	Down syndrome (trisomy 21)	Characteristic facies (flat facial profile, small ears, upslanting palpebral fissures, epicanthal folds), large tongue, atrioventricular canal defects, duodenal atresia, Hirschsprung disease, leukemia, single transverse palmar crease, intellectual disability, low muscle tone, early-onset Alzheimer disease
	Turner syndrome (45, X)	Short stature, webbed neck, low-set ears, low posterior hairline, wide-set nipples, coarctation of aorta, bicuspid aortic valve, puffy hands/feet at birth, ovarian insufficiency, infertility
	Klinefelter syndrome (47, XXY)	Tall stature, gynecoid habits (fat distributed around hips and thighs), decreased testicular volume, infertility
	Trisomy 13	Microcephaly, holoprosencephaly and other midline defects, heart defects, polydactyly, aplasia cutis, intellectual disability
	Trisomy 18	Microcephaly, prominent occiput, micrognathia, characteristic facial features, heart defects, clenched fist with overlapping fingers, rocker-bottom feet, intellectual disability
Deletion syndromes	22q11.2 deletion syndrome	Phenotype falls on a spectrum: DiGeorge syndrome phenotype: parathyroid hypoplasia causing hypocalcemia, thymic hypoplasia causing immunodeficiency Velocardiofacial syndrome phenotype: Characteristic facial features (prominent tubular nose and/or bulbous nasal tip, retrognathia), nasal speech, cleft palate, outflow tract defects of heart (e.g., tetralogy of Fallot)
Triplet repeat disorders	Fragile X syndrome	Intellectual disability, large testes starting in puberty, long face, large ears
Imprinting disorders	Prader-Willi syndrome	Hypotonia, infantile failure to thrive followed by hyperphagia and obesity starting in childhood, intellectual disability, small hands and feet, hypogonadism
	Angelman syndrome	Intellectual and motor disability, ataxia, epilepsy, inappropriate laughter, fair complexion
	Beckwith-Wiedemann Syndrome	Omphalocele, large tongue, overgrowth, hemihypertrophy, neonatal hypoglycemia, ears with linear indentations on lobes and posterior pits, predisposition to Wilms tumor and hepatoblastoma
Connective-tissue disorders	Ehlers-Danlos syndrome, hypermobility type	Joint hyperextensibility, dislocations or subluxations, joint pain, female predominance (Note: no known genetic cause, but sometimes runs in families)
	Marfan syndrome	Tall, thin, long arms and legs, scoliosis, characteristic facial features (deep-set eyes, flat cheekbones, recessed jaw, downslanting palpebral fissures), aortic dilation/dissection/rupture, mitral-valve prolapse, lens dislocation
Syndromes with congenital heart defects	Noonan syndrome	Short stature, characteristic facial features (triangular face, downslanting palpebral fissures, epicanthal folds, hypertelorism), short and/or webbed neck, low- set posteriorly rotated ears, heart disease (including pulmonic stenosis and hypertrophic cardiomyopathy), developmental delays

The conditions listed above, with the exception of hypermobility-type Ehlers-Danlos syndrome, are examples of Mendelian disorders. This term means that a disease has an identifiable genetic cause that leads to a predictable pattern of inheritance (these are sometimes called “single-gene” disorders). Non-Mendelian conditions are those that might have a genetic influence, but lack a predictable inheritance pattern or a single, identified genetic cause. For example, most cases of isolated congenital heart disease and nonsyndromic autism seem to fall into this category. Traditionally, such conditions have been thought to be caused by a combination of genetic risk, environmental influences, and stochastic developmental processes. However, some evidence suggests that some of these cases might in fact be Mendelian but caused by the accumulated burden of variants in two or more different genes.

Research

Landmark clinical trials and other important studies

Research

Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease

Kim J et al. N Engl J Med 2019.

N-of-1 study of milasen, a targeted antisense oligonucleotide therapy developed for a specific splicing variant at the time known in just one child (Mila).

Oligogenic Inheritance of a Human Heart Disease Involving a Genetic Modifier

Gifford CA et al. Science 2019.

In a family with multiple offspring affected by childhood-onset cardiomyopathy, symptomatic children were found to have a genetic variant in each of three genes, two of which were inherited from one parent and one of which was inherited from the other parent. Using the CRISPR system to introduce these variants into mice suggested that only the combination of all three variants caused the phenotype - an apparent example of “oligogenic” inheritance.

Prenatal Correction of X-Linked Hypohidrotic Ectodermal Dysplasia

Schneider H et al. N Engl J Med 2018.

A case report of three boys prenatally diagnosed with X-liked hypohidrotic ectodermal dysplasia who were prenatally treated with a recombinant protein containing the receptor-binding domain of ectodysplasin A that had proof of efficacy in mice. The boys were subsequently born with a normal ability to sweat.

Congenital Heart Surgery on In-Hospital Mortality in Trisomy 13 and 18

Kosiv KA et al. Pediatrics 2017.

This retrospective review of more than 1600 individuals with Trisomy 13 or Trisomy 18 demonstrated lower in-hospital mortality for those offered cardiac surgery.