| DISORDER |
GENE(S) |
DESCRIPTION |
REFERENCES(PMID) |
| Canavan disease |
ASPA |
Canavan disease is a neurodegenerative leukodystrophy which
disrupts the ability of the neurons to transmit messages. Canavan
disease is caused by biallelic pathogenic variants in the ASPA gene.
Most commonly, symptoms of Canavan disease begin in infancy
with significant developmental delay, weak muscle tone, irritability
and other behavioral issues, and macrocephaly; this is known as the
neonatal/infantile type. Affected individuals often pass away before
early adulthood. There is no cure for Canavan disease, but medical
surveillance and care may help to improve some symptoms and overall
condition of life; treatments such as adeno-associated virus-mediated
(AAV) gene therapy are being actively researched. Individuals with
the mild/juvenile form of Canavan disease usually present with mild
developmental delay and may go undiagnosed as this is often their only
symptom; lifespan is unaffected. The prevalence of Canavan disease in
the Ashkenazi Jewish population is estimated to be between 1 in 6,400
to 1 in 13,500 newborns and is less common in the general population. |
35636725, 30535831, 37601414 |
| Noonan syndrome |
PTPN11, SHOC, SOS2, BRAF, RIT1, SOS1, KRAS, RAS1, NRAS |
Noonan syndrome is one of a group of conditions known as
RASopathies. Several genes are associated with Noonan syndrome;
pathogenic variants in PTPN11 causes about 50% of all cases. In
the prenatal period, increased nuchal translucency is suggestive of
Noonan syndrome. Affected individuals typically present in childhood
with characteristic facial features, short stature, a broad and webbed
neck, developmental delay, and congenital heart defects. The most
common heart defect associated with the disorder is pulmonary valve
stenosis. Many individuals also have skeletal issues such as scoliosis,
learning difficulties, delayed puberty, and excessive bruising. Children
with Noonan syndrome are at increased risk for leukemia. There is
no cure for Noonan syndrome, but medical surveillance and care may
help to improve some symptoms and overall condition of life. Noonan
syndrome occurs in 1 in 1,000 to 1 in 2,500 individuals but may be
underdiagnosed. |
20301303, 32022400, 35246453 |
| Sotos syndrome |
NSD1 |
Sotos syndrome is an inherited disorder characterized by three hallmark
features: distinctive facial features, developmental delay and intellectual
disability, and macrocephaly with accelerated growth in childhood.
Sotos syndrome is caused by pathogenic variants in the NSD1 gene.
Other common symptoms include low muscle tone, increased risk for
behavioral disorders, issues with speech and language, scoliosis, and
cardiac issues. Brain imaging is often abnormal. There is no cure for
Sotos syndrome, but medical surveillance and care may help to improve
some symptoms and overall condition of life. The prevalence of Sotos
syndrome is estimated to be 1 in 14,000 individuals. |
20301652, 31479583 |
| CHARGE syndrome |
CHD7 |
CHARGE syndrome is an inherited disorder characterized by specific
congenital anomalies: coloboma, choanal atresia, growth retardation,
and cardiac, genital, and ear abnormalities. The clinical diagnosis is
often made shortly after birth or even prenatally when a physician
observes several of these anomalies in combination. Many individuals
have distinctive facial features, vision and hearing loss, and lifelong
gastrointestinal problems. CHARGE syndrome is caused by pathogenic
variants in the CHD7 gene. There is no cure for CHARGE syndrome, but
medical surveillance and care may help to improve some symptoms
and overall condition of life. The prevalence of CHARGE syndrome is
estimated to be 1 in 10,000 births. |
32644625, 32625235, 32384900 |
| Cornelia de Lange syndrome |
SMC1A, SMC3, RAD21, NIPBL, HDAC8 |
Cornelia de Lange syndrome (CdLS) is an inherited disorder with a
wide range of symptoms. There are many types of CdLS caused by
pathogenic variants in several genes. The hallmark features of the
disorder include characteristic facial features, restricted growth
beginning in the prenatal period, excessive hair growth, and missing
or abnormal fingers. Affected individuals have mild to moderate
intellectual disability and are at increased risk for behavioral issues.
Other symptoms such as hearing loss, myopia, and gastrointestinal
issues are common. There is no cure for CdLS, but medical surveillance
and care may help to improve some symptoms and overall condition
of life. The prevalence of Cornelia de Lange syndrome may be as high
as 1 in 10,000 as the symptoms can be mild, and it is likely that many
individuals go undiagnosed. |
20301283, 34356091 |
| Joubert syndrome |
CC2D2A, CEP290, OFD1, TMEM67, AHI1 |
Joubert syndrome is an inherited disorder that affects various parts
of the body. There are multiple genetically distinct types of Joubert
syndrome caused by pathogenic variants in genes such as CEP290
and TMEM67. Affected individuals have a hallmark feature known as
the molar tooth sign, a combination of brain abnormalities which can
be seen on brain imaging studies. Due to these brain abnormalities,
individuals will often present with low muscle tone, difficulty in
coordinating movements, breathing problems, slow growth rate,
distinctive facial features, and abnormal eye movements. Other features
include kidney, liver, and bone problems. Intellectual disability or
learning problems are associated with Joubert syndrome. Treatment
is symptomatic. The combined prevalence of all types of Joubert
syndrome is about 1 in 100,000 newborns. |
32139166, 31710777, 36803942 |
| Coffin-Siris syndrome |
SMARCA4, ARID1A, ARID1B, SMARCB1 |
Coffin-Siris syndrome (CSS) is an inherited disorder characterized by
aplasia of the fifth digit; other symptoms include characteristic facial
features, developmental delay, low muscle tone, and atypical hair
growth. Some individuals with CSS have gastrointestinal and cardiac
issues. There are multiple genes associated with CSS such as ARID1B
which accounts for almost 40% of diagnoses. There is no cure for CSS,
but medical surveillance and care may help to improve some symptoms
and overall condition of life. The worldwide prevalence of CSS is
unknown, with approximately 200 patients reported in the literature. |
23556151, 34205270 |
| Rett syndrome |
MECP2 |
Rett syndrome is a progressive neurodevelopmental disorder affecting
mostly female children; it is characterized by normal development
for the first 18 months of age followed by rapid regression of
developmental skills. During the regression period, individuals
experience seizures, hand wringing, acquired microcephaly, ataxia, and
autism-like features. Approximately 85% of females with Rett syndrome
have MECP2 variants detected by sequence analysis and approximately
10% have copy number variants in the gene. The prevalence of Rett
syndrome in females is estimated to be as high as 5 in 100,000.
Treatment is symptomatic, although there are ongoing trials for Rettspecific
medications.
Most pathogenic MECP2 variants in males cause severe neonatal
encephalopathy, seizures, abnormal tone, and breathing issues; death
often occurs before 2 years of age. MECP2 duplication, however, affects
males less severely but still causes seizures, intellectual disability, and
hypotonia. Generally, females with a heterozygous MECP2 duplication
are asymptomatic but may have neuropsychiatric symptoms with
normal intellectual ability. |
36642718, 37291210, 36056801, 30929312, 20301670 |
| Smith-Lemli-Opitz syndrome |
DHCR7 |
Smith-Lemli-Opitz syndrome (SLOS) is an inherited metabolic condition
in which an individual’s body cannot properly make and use cholesterol
due to the deficiency of the enzyme 7-dehydrocholesterol reductase.
SLOS is caused by biallelic pathogenic variants in DHCR7. Cholesterol
is important for the normal development of many organs in the body
including the brain. Affected individuals with severe SLOS may be born
small, have slow growth or development, and/or have a small head size.
Individuals may present with cleft palate, heart defects, extra fingers
and toes, fused second and third toes, and severely affected males may
have poorly formed genitals. As these children grow, they may begin
to exhibit behavioral problems such as hyperreactivity, irritability, or
autism spectrum behaviors. Individuals with SLOS may have moderate
to severe intellectual disability. Individuals with milder forms of SLOS
may have less severe symptoms, with mild to no intellectual disability.
Severely affected individuals may have a shortened lifespan or pass
away in infancy. There is no cure for SLOS, but medical surveillance
and care may help to improve some symptoms and overall condition
of life. There is some evidence that cholesterol supplementation could
be beneficial. SLOS is estimated to occur in about 1 in 20,000 to 1
in 40,000 newborns; however, the actual occurrence may be higher
because females and mildly affected individuals may be undiagnosed.
SLOS is more common in Caucasian people and less common in people
of African or Asian ancestry. |
20301322, 31005410, 33115520 |
| Helsmoortelvan der Aa syndrome |
ADNP |
Helsmoortel-van der Aa syndrome (HVDAS) is an inherited
disorder that affects primarily the brain and face and is caused
by pathogenic variants in the ADNP gene. Individuals with HVDAS
severe developmental delay, a degree of intellectual disability, and
characteristic facial features such as a high hairline, ptosis, broad
nasal bridge, and thin vermilion of the upper lip. Brain imaging is often
abnormal. Autism spectrum disorder and behavioral problems are
common; other symptoms include gastrointestinal and vision problems,
hearing loss, and seizures. There is no cure for HVDAS, but medical
surveillance and care may help to improve some symptoms and overall
condition of life; one recent study investigated the effect of low-dose
ketamine on patients with HVDAS and reported nominal symptom
improvement. While the worldwide prevalence of HVDAS is unknown,
the disorder is one of the most common causes of autism spectrum
disorder. |
27054228, 36082574, 36119806 |
| PTEN hamartoma tumor syndrome |
PTEN |
PTEN hamartoma tumor syndrome is a spectrum of overgrowth
disorders caused by pathogenic variants in the PTEN gene: Cowden
syndrome, Bannayan-Riley-Ruvalcaba syndrome, and PTEN-related
Proteus syndrome. Individuals with Cowden syndrome (CS) are at
high risk for breast cancer in mid-adulthood as well as thyroid, renal,
and endometrial cancer. Some patients present in childhood with
macrocephaly, developmental delay and/or autism spectrum disorder,
and benign skin tumors; gastrointestinal polyps and pediatric-onset
thyroid cancer is common. Bannayan-Riley-Ruvalcaba syndrome
(BRRS) and PTEN-related Proteus syndrome (PS) both present at
birth; BRRS often presents with developmental delay, macrocephaly,
and skin findings while PS is characterized by overgrowth of multiple
tissues. Treatment for PTEN hamartoma tumor syndrome is based on
symptoms and includes increased cancer screening. The prevalence of
PTEN hamartoma tumor syndrome is likely underestimated due to the
variable and sometimes mild symptoms; Cowden syndrome occurs in
approximately 1 in 200,000 individuals. |
20301661, 31433956, 34983360 |
