The 12 days of Christmas are upon us!
To partake in the festive holiday spirit, we wanted to highlight 12 genetic conditions from chromosome 12. There are hundreds of genetic conditions that arise because of variants on chromosome 12, but below are twelve that all include some form of intellectual disability (ID)/developmental delay (DD) in children.
Of course, they also have additional features that go along with the ID/DD, and those are highlighted below. Most importantly, many of these groups have family support websites that discuss important medical interventions to help children with the given condition reach their full potential!
1. Trisomy 12p syndrome:
This condition is caused by extra genetic material from the p arm (also called the short arm) of chromosome 12. In addition to ID, symptoms of this condition include abnormal muscle tone, seizures, and unique facial features. Low blood sugar, hearing loss, behavioral issues, vision and dental problems, sleep disturbances, sparse hair, and a large tongue have also been reported.1-3
2. Lamb-Shaffer syndrome:
This condition is caused by variants that make one copy of the SOX5 gene not work correctly (called pathogenic variants). Symptoms include poor expressive speech, mildly unique facial features, low muscle tone, birth defects, and behavioral concerns. Individuals with this condition are described as having very happy and content personalities.4
As the name implies, this condition is caused by pathogenic variants in the MED13L gene. Symptoms include significant language impairment, low muscle tone, unusual or uncoordinated gait (ataxia), unique facial features, and heart defects in some individuals.5
4. Noonan syndrome and Cardiofaciocutaneous syndrome:
These conditions are caused by pathogenic variants in the KRAS gene. The conditions have overlapping symptoms and may actually be the same genetic condition with a spectrum of features.
Noonan syndrome affects as many as 1 in 1,000 people and approximately 50% of people with Noonan syndrome are mis- or underdiagnosed! Noonan syndrome is most often characterized by short stature, heart abnormalities, and unique facial features. A broad neck, undescended testicles, and eye abnormalities may also occur.6
Cardiofaciocutaneous (CFC) syndrome is characterized by heart abnormalities, unique facial features, a variety of skin changes (hyperkeratosis, ichthyosis, hemangiomas), hair differences (sparse, thick, fine, woolly, or brittle), and abnormal/underdeveloped nails. A potential increased risk for cancers has also been reported.7
5. Holt-Oram syndrome:
The TBX5 gene is linked to Holt-Oram syndrome. The symptoms of this condition include upper-limb abnormalities of the radial, ulnar, or carpel bones, heart defects, and heart conduction defects. The upper-limb abnormalities can be mild and affect one or both arms and include under development, or no development, of the arm and hand bones.8
6. Sanfilippo syndrome type D:
Also called mucopolysaccharidosis type 3D, is caused by pathogenic variants in both copies of the GNS gene. This is a lysosomal storage disorder caused by impaired break-down of heparan sulfate (which is found naturally in the body) and results in a progressive speech delay, behavioral problems, sleep dysfunction, developmental regression, seizures, coarse facies, hearing loss, and vision impairment. The good news is that many lysomsomal storage disorders can be treated with enzyme replacement therapy (ERT)(unfortunately, type D currently does not). Additionally, individuals can undergo carrier testing for Sanfilippo syndrome, to see if they or their reproductive partner is a carrier. If both parents are carriers, there is a 25% chance each pregnancy will have the condition.9
7. Pallister-Killian syndrome:
This condition is caused by tetrasomy (having four copies of genetic material, opposed to the typical two) of 12p, usually in a mosaic pattern. Mosaicism means not all cells in the body have this finding (think of a “mosaic” tile pattern with some black and some white tiles). The symptoms of this condition include seizures, streaks of lighter or darker skin (hypo-or hyper-pigmentation), and unique facial features including prominent forehead with sparse scalp hair, widely spaced eyes, flat nasal bridge, and short neck. Cardiovascular, gastrointestinal, and genitourinary anomalies have also been reported. Children with this condition are reported to have “laid back” personalities.10
8. GRIN2B-related disorders:
Pathogenic GRIN2B gene variants cause a spectrum of conditions. Symptoms vary but can include seizures, ADHD, autism spectrum disorder (ASD), and schizophrenia. Some individuals have an epileptic encephalopathy presenting with typical neurodevelopment followed by cognitive decline and motor delay with seizure onset. Other individuals have some of the symptoms, but without seizures.11-14
9. Coffin-Siris syndrome type 6:
This condition, also called Coffin-Siris-like condition or ARID2-related ID, is caused by pathogenic variants in the ARID2 gene. The symptoms of this condition include ASD and ADHD. Physical features can include a smaller pinky finger (mild fifth digit hypoplasia) with small nails, short stature, low muscle tone, and Wormian bones. Facial features can consist of wide mouth with thick and everted lips, high forehead, and broad and/or flat nasal bridge.15-18
10. Kabuki syndrome:
Named after make-up of Kabuki actors, a form of Japanese theater, Kabuki syndrome is caused by variants in the KMT2D gene that cause it not to work properly. This condition presents with minor skeletal anomalies, persistence of fetal fingertip pads, postnatal growth delay, and unique facial features (resembling Kabuki make-up; hence the name). Physical birth defects may include heart defects, genitourinary anomalies, cleft lip and/or palate, and widely spaced or missing teeth. Immune and autoimmune conditions, seizures, endocrine abnormalities, feeding concerns, and hearing loss have also been reported.19
11. Stickler syndrome:
The COL2A1 gene has a role in collagen formation and function. Pathogenic variants in COL2A1 can cause a spectrum of collagen-related disorders; the most recognized being Stickler syndrome. The symptoms of Sickler syndrome may include cleft in the roof of the mouth (palate), a set of facial/head abnormalities called Peirre Robin sequence, broad or flat nasal bridge, small and upturned nasal tip, and small/regressed chin, hearing loss, and skeletal and/or eye anomalies. Like other conditions on this list, Stickler syndrome is underdiagnosed, and some people only have one symptom (like joint problems).20
12. Phenylketonuria (PKU):
This condition is best known through newborn screening testing (sometimes referred to as the “PKU test” although newborn screening panels evaluate for many more conditions than just PKU). Pathogenic variants that affect BOTH copies of the PAH gene cause phenylalanine hydroxylase deficiency (PAH deficiency). PAH deficiency results in a spectrum of disorders, most notably PKU, related to the inability to breakdown the amino acid phenylalanine. In classic, untreated PKU, individuals have profound ID. Treatment for PKU begins in infancy, and when treated effectively, significantly decreases the risk of ID.21 Carrier screening during pregnancy is also available for PKU.
As you can tell from the details, many of these conditions are similar to one another (they have overlapping features like heart defects and developmental delay) yet have different specific causes. This underscores the importance of having a broad genetic test (such as chromosomal microarray or MyDevelopingChild’s Essential test) as compared to a single specific test (such as fragile X syndrome) when a child has developmental concerns. If you are worried about your child’s development, speak to your child’s healthcare provider or a genetic counselor today to learn more. Pinpointing the diagnosis can provide important information to personalize and improve his or healthcare as you head into the new year.
Izumi K, et al. 2012. PMID: 23169682
Segel R, et al. 2006. PMID: 16502429
Rauch A, et al. 1996. PMID: 8723117
Fukushi D, et al. 2018. PMID: 29477873
Asadollahi R, et al. 2013. PMID: 23403903
Allanson JE, Roberts AE. 2019. PMID: 20301303
Rauen KA. 2016. PMID: 20301365
McDermott DA, Fong JC, Basson CT. 2019. PMID: 20301290