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

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

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

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

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

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

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

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

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

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

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