Single-gene conditions

Imagine our genome as a script, written in the language of DNA. DNA, or deoxyribonucleic acid, is the molecule that carries all the genetic instructions for building and maintaining an organism. Within its long, double-helix structure are segments called genes. Each gene consists of a specific sequence of DNA that contains the instructions for making proteins, which are the building blocks and one of the most important functional molecules in our bodies. Most of the time, these genes work together smoothly. However, sometimes a variation occurs in just one gene, throwing everything off balance and leading to a wide range of conditions.

Single-gene (or monogenic) conditions are caused by variations in one particular gene. These variations alter the DNA sequence of that specific gene, affecting the protein it codes for. The consequences of these genetic changes depend on the protein’s function. While each individual single-gene condition is rare, collectively, they affect about one percent of the population.

These conditions can be categorized as follows:

Dominant disorders: These occur when an individual has one “mutant” copy of the relevant gene and one healthy copy. The effects of the mutant allele override those of the healthy allele, leading to disease symptoms. An example is Noonan syndrome.
Recessive disorders: These require two copies of the “mutant” gene (homozygous state) for symptoms to manifest. An example is cystic fibrosis.
Sex Chromosome-linked disorders: These affect genes on the sex chromosomes (X or Y). X-linked disorders can be either recessive or dominant. CHILD syndrome is an example of an X-linked dominant disorder.

With MONO technology we can detect 202 dominant single-gene conditions caused by de novo variants in 155 target genes. A de novo variation is a term used to describe a change in the DNA sequence of a gene that is seen for the first time in a person and has not appeared in previous generations. A de novo variation can explain how a person can have a genetic condition that did not occur in their parents.

Some dominant single-gene conditions screened for with MONO aren’t typically associated with abnormal prenatal ultrasound findings (especially in the first trimester) or can be discovered only in the late second/third trimester or after delivery.

Please note that syndromes can exhibit a wide range of clinical manifestations. The description provided here is a general overview, highlighting the common clinical features typically associated with these syndromes. Individual cases may vary significantly in their presentation and severity.

1. Achondrogenesis, type II or hypochondrogenesis; ACG2 (OMIM 200610)

COL2A1 gene (OMIM 120140) on chromosome 12q13; AD

Achondrogenesis type II (ACG2) is characterized by severe micromelic dwarfism with small chest and prominent abdomen, incomplete ossification of the vertebral bodies, and disorganization of the costochondral junction. ACG2 is an autosomal dominant trait occurring mostly as new mutations. However, somatic and germline mosaicism have been reported.

2. Achondroplasia; ACH (OMIM 100800)

FGFR3 gene (OMIM 134934) on chromosome 4p16.3; AD

Achondroplasia (ACH) is the most frequent form of short-limb dwarfism. Affected individuals exhibit short stature caused by rhizomelic shortening of the limbs, characteristic facies with frontal bossing and midface hypoplasia, exaggerated lumbar lordosis, limitation of elbow extension, genu varum, and trident hand.

3. Acrodysostosis 1, with or without hormone resistance; ACRDYS1 (OMIM 101800)

PRKAR1A gene (OMIM 188830) on chromosome 17q24; AD

Acrodysostosis-1 (ACRDYS1) is a form of skeletal dysplasia characterized by short stature, severe brachydactyly, facial dysostosis, and nasal hypoplasia. Affected individuals often have advanced bone age and obesity. Laboratory studies show resistance to multiple hormones, including parathyroid, thyrotropin, calcitonin, growth hormone-releasing hormone, and gonadotropin. However, not all patients show endocrine abnormalities.

4. Alagille syndrome; ALGS

Alagille syndrome (ALGS) is a complex multisystem disorder involving primarily the liver, heart, eyes, face, and skeleton. The clinical features are highly variable, even within families. The major clinical manifestations of ALGS are cholestasis, characterized by bile duct paucity on liver biopsy; congenital cardiac defects, primarily involving the pulmonary arteries; posterior embryotoxin in the eye; typical facial features; and butterfly vertebrae. Renal and central nervous abnormalities also occur. Mortality is approximately 10%, with vascular accidents, cardiac disease, and liver disease accounting for most of the deaths.

4.1 Alagille syndrome 1; ALGS1 (OMIM 118450)

JAG1 gene (OMIM 601920) on chromosome 20p12; AD

A form of Alagille syndrome.

4.2 Alagille syndrome 2; ALGS2 (OMIM 610205)

NOTCH2 gene (OMIM 600275) on chromosome 1p12; AD

A form of Alagille syndrome.

5. Alexander disease; ALXDRD (OMIM 203450)

GFAP gene (OMIM 137780) on chromosome 17q21; AD

In decreasing order of frequency, 3 forms of Alexander disease (ALXDRD) are recognized, based on age of onset: infantile, juvenile, and adult. Younger patients typically present with seizures, megalencephaly, developmental delay, and spasticity. In older patients, bulbar or pseudobulbar symptoms predominate, frequently accompanied by spasticity. The disease is progressive, with most patients dying within 10 years of onset. Imaging studies of the brain typically show cerebral white matter abnormalities, preferentially affecting the frontal region. All 3 forms have been shown to be caused by mutations in the GFAP gene.

6. Alternating hemiplegia of childhood 1; AHC1 (OMIM 104290)

ATP1A2 gene (OMIM 182340) on chromosome 1q23; AD

Alternating hemiplegia of childhood 1 (AHC1) is a rare syndrome of episodic hemi- or quadriplegia lasting minutes to days. Most cases are accompanied by dystonic posturing, choreoathetoid movements, nystagmus, other ocular motor abnormalities, autonomic disturbances, and progressive cognitive impairment.

7. Andersen syndrome (OMIM 170390)

KCNJ2 gene (OMIM 600681) on chromosome 17q24; AD

Andersen cardiodysrhythmic periodic paralysis, also known as Andersen syndrome or Andersen-Tawil syndrome, is an autosomal dominant multisystem channelopathy characterized by periodic paralysis, ventricular arrhythmias, and distinctive dysmorphic facial or skeletal features. Hypoplastic kidney and valvular heart disease have also been reported. The disorder shows marked intrafamilial variability and incomplete penetrance.

8. Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis; ABS2 (OMIM 207410)

FGFR2 gene (OMIM 176943) on chromosome 10q26; AD

The Antley-Bixler syndrome (ABS) is an exceptionally rare craniosynostosis syndrome characterized by radiohumeral synostosis present from the perinatal period. There is a wide spectrum of anomalies seen in ABS, including midface hypoplasia, choanal stenosis or atresia, and multiple joint contractures. Mortality has been reported to be as high as 80% in the neonatal period, primarily due to airway compromise, and prognosis improves with increasing age.

9. Apert syndrome (OMIM 101200)

FGFR2 gene (OMIM 176943) on chromosome 10q26; AD

Apert syndrome is a congenital disorder characterized primarily by craniosynostosis, midface hypoplasia, and syndactyly of the hands and feet with a tendency to fusion of bony structures. Most cases are sporadic, but autosomal dominant inheritance has been reported.

10. Atelosteogenesis; AO

Atelosteogenesis is a lethal chondrodysplasia characterized by distal hypoplasia of the humeri and femurs, hypoplasia of the midthoracic spine, occasionally complete lack of ossification of single hand bones, and the finding in cartilage of multiple degenerated chondrocytes encapsulated in fibrous tissue.

10.1 Atelosteogenesis, type I; AO1 (OMIM 108720)

FLNB gene (OMIM 603381) on chromosome 3p14; AD

A form of Atelosteogenesis.

10.2 Atelosteogenesis, type III; AO3 (OMIM 108721)

FLNB gene (OMIM 603381) on chromosome 3p14; AD

A form of Atelosteogenesis.

11. Au-Kline syndrome; AUKS (OMIM 616580)

HNRNPK gene (OMIM 600712) on chromosome 9q21; AD

Au-Kline syndrome (AUKS) is an autosomal dominant disorder characterized by hypotonia, global developmental delay, characteristic facies (long palpebral fissures, shallow orbits, ptosis, a broad nasal bridge, hypoplastic alae nasi, downturned corners of the mouth and a long face), congenital heart defects, genitourinary abnormalities, skeletal abnormalities, and variable other congenital malformations.

12. Coffin-Siris syndrome; CSS

Coffin-Siris syndrome is a multiple malformation syndrome characterized by mental retardation associated with coarse facial features, hypertrichosis, sparse scalp hair, and hypoplastic or absent fifth fingernails or toenails. Other more variable features may include poor overall growth, craniofacial abnormalities, spinal anomalies, and congenital heart defects.

12.1 Coffin-Siris syndrome 1; CSS1 (OMIM 135900)

ARID1B gene (OMIM 614556) on chromosome 6q25; AD

A form of Coffin-Siris syndrome.

12.2 Coffin-Siris syndrome 2 / MENTAL RETARDATION, AUTOSOMAL DOMINANT 14; CSS2 (OMIM 614607)

ARID1A gene (OMIM 603024) on chromosome 1p36; AD

A form of Coffin-Siris syndrome.

12.3 Coffin-Siris syndrome 3 / MENTAL RETARDATION, AUTOSOMAL DOMINANT 15; CSS3 (OMIM 614608)

SMARCB1 gene (OMIM 601607) on chromosome 22q11; AD

A form of Coffin-Siris syndrome.

12.4 Coffin-Siris syndrome 4 / MENTAL RETARDATION, AUTOSOMAL DOMINANT 16; CSS4 (OMIM 614609)

SMARCA4 gene (OMIM 603254) on chromosome 19p13; AD

A form of Coffin-Siris syndrome.

12.5 Coffin-Siris syndrome 5; CSS5 (OMIM 616938)

SMARCE1 gene (OMIM 603111) on chromosome 17q21; AD

A form of Coffin-Siris syndrome.

13. Helsmoortel-van der Aa syndrome / MENTAL RETARDATION, AUTOSOMAL DOMINANT 28; HVDAS (OMIM 615873)

ADNP gene (OMIM 611386) on chromosome 20q13; AD

Helsmoortel-Van der Aa syndrome (HVDAS) is a neurodevelopmental disorder characterized by impaired intellectual development/motor delay, autism spectrum disorder, facial dysmorphisms, hypotonia, congenital heart disease, visual difficulties, and gastrointestinal issues.

14. Bainbridge-Ropers syndrome; BRPS (OMIM 615485)

ASXL3 gene (OMIM 615115) on chromosome 18q12; AD

Bainbridge-Ropers syndrome (BRPS) is a developmental disorder characterized by delayed psychomotor development, severe intellectual disability with poor or absent speech, hypotonia, feeding difficulties, poor growth, and dysmorphic facial features.

15. Baraitser-Winter syndrome; BRWS

Baraitser-Winter syndrome (BRWS) is a rare developmental phenotype characterized by the combination of hypertelorism, broad nose with large tip and prominent root, congenital nonmyopathic ptosis, ridged metopic suture, arched eyebrows, iris or retinal coloboma, sensorineural deafness, shoulder girdle muscle bulk and progressive joint stiffness, and pachygyria with anteroposterior severity gradient, rarely lissencephaly or neuronal heterotopia. Cleft lip and palate, hallux duplex, congenital heart defects and renal tract anomalies are seen in some cases. Microcephaly may develop with time. Early muscular involvement, occasionally with congenital arthrogryposis, may be present. Intellectual disability and epilepsy are variable in severity and largely correlate with central nervous system anomalies.

15.1 Baraitser-Winter syndrome 1; BRWS1 (OMIM 243310)

ACTB gene (OMIM 102630) on chromosome 7p22; AD

A form of Baraitser-Winter syndrome.

15.2 Baraitser-Winter syndrome 2; BRWS2 (OMIM 614583)

ACTG1 gene (OMIM 102560) on chromosome 17q25; AD

A form of Baraitser-Winter syndrome.

16. Beare-Stevenson cutis gyrata syndrome; BSTVS (OMIM 123790)

FGFR2 gene (OMIM 176943) on chromosome 10q26; AD

Beare-Stevenson cutis gyrata syndrome (BSTVS) is an autosomal dominant condition characterized by the furrowed skin disorder of cutis gyrata, acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities, and early death.

17. Bent bone dysplasia syndrome; BBDS1 (OMIM 614592)

FGFR2 gene (OMIM 176943) on chromosome 10q26; AD

Bent bone dysplasia syndrome-1 (BBDS1) is a perinatal lethal skeletal dysplasia characterized by poor mineralization of the calvarium, craniosynostosis, dysmorphic facial features, prenatal teeth, hypoplastic pubis and clavicles, osteopenia, and bent long bones.

18. Blepharophimosis-impaired intellectual development syndrome; BIS (OMIM 619293)

SMARCA2 gene (OMIM 600014) on chromosome 9p24; AD

Blepharophimosis-impaired intellectual development syndrome (BIS) is a congenital disorder characterized by a distinct facial appearance with blepharophimosis and global development delay. Affected individuals have delayed motor skills, sometimes with inability to walk, and impaired intellectual development with poor or absent speech; some patients show behavioral abnormalities. There are recognizable facial features, including epicanthal folds, sparse eyebrows, broad nasal bridge, short nose with downturned tip, and open mouth with thin upper lip. Other more variable features include distal skeletal anomalies, feeding difficulties with poor growth, respiratory infections, and hypotonia with peripheral spasticity.

19. Bohring-Opitz syndrome; BOPS (OMIM 605039)

ASXL1 gene (OMIM 612990) on chromosome 20q11; AD

Bohring-Opitz syndrome (BOPS) is a malformation syndrome characterized by severe intrauterine growth retardation, poor feeding, profound mental retardation, trigonocephaly, prominent metopic suture, exophthalmos, nevus flammeus of the face, upslanting palpebral fissures, hirsutism, and flexion of the elbows and wrists with deviation of the wrists and metacarpophalangeal joints.

20. Boomerang dysplasia; BOOMD (OMIM 112310)

FLNB gene (OMIM 603381) on chromosome 3p14; AD

Boomerang dysplasia (BOOMD) is a perinatal lethal osteochondrodysplasia characterized by absence or underossification of the limb bones and vertebrae.

21. Bosch-Boonstra-Schaaf optic atrophy syndrome; BBSOAS (OMIM 615722)

NR2F1 gene (OMIM 132890) on chromosome 5q15; AD

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an autosomal dominant disorder characterized by delayed development, moderately impaired intellectual development, and optic atrophy. Most patients also have evidence of cerebral visual impairment. Dysmorphic facial features are variable and nonspecific.

22. Campomelic dysplasia; CMPD (OMIM 114290)

SOX9 gene (OMIM 608160) on chromosome 17q24; AD

Campomelic dysplasia (CMPD) is an autosomal dominant skeletal dysplasia characterized by congenital shortness and bowing of long tubular bones, especially in the lower extremities, as well as by hypoplastic scapulae, narrow iliac wings, and nonmineralized thoracic pedicles. CMPD is often lethal in the first year of life, due to respiratory insufficiency related to small chest size and tracheobronchial hypoplasia.

23. Cardiac, facial, and digital anomalies with developmental delay; CAFDADD (OMIM 618164)

TRAF7 gene (OMIM 606692) on chromosome 16p13; AD

Cardiac, facial, and digital anomalies with developmental delay (CAFDADD) is a multisystemic developmental disorder with variable cardiac and digital anomalies and facial dysmorphism. Some patients may have seizures and ocular/aural abnormalities.

24. Cardiofaciocutaneous syndrome; CFC

Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects, and mental retardation. The heart defects include pulmonic stenosis, atrial septal defect, and hypertrophic cardiomyopathy. Some patients have ectodermal abnormalities such as sparse and friable hair, hyperkeratotic skin lesions, and a generalized ichthyosislike condition. Typical facial characteristics include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices.

24.1 Cardiofaciocutaneous syndrome; CFC1 (OMIM 115150)

BRAF gene (OMIM 164757) on chromosome 7q34; AD

A form of Cardiofaciocutaneous syndrome.

24.2 Cardiofaciocutaneous syndrome 2; CFC2 (OMIM 615278)

KRAS gene (OMIM 190070) on chromosome 12p12; AD

A form of Cardiofaciocutaneous syndrome.

24.3 Cardiofaciocutaneous syndrome 3; CFC3 (OMIM 615279)

MAP2K1 gene OMIM 176872) on chromosome 15q22; AD

A form of Cardiofaciocutaneous syndrome.

24.4 Cardiofaciocutaneous syndrome 4; CFC4 (OMIM 615280)

MAPK2K2 gene (OMIM 601263) on chromosome 19p13; AD

A form of Cardiofaciocutaneous syndrome.

25. Cerebellar dysfunction with variable cognitive and behavioral abnormalities; CECBA (OMIM 614756)

CAMTA1 gene (OMIM 611501) on chromosome 1p36; AD

Cerebellar dysfunction with variable cognitive and behavioral abnormalities (CECBA) is an autosomal dominant neurologic disorder with significant phenotypic heterogeneity, even within families. The disorder is most often diagnosed through genetic analysis with retrospective clinical phenotyping. Symptom onset is usually in early childhood, although later onset, even in adulthood, has been reported. Most affected individuals show global developmental delay from early childhood, particularly of motor and language skills. Many have mild intellectual disability; behavioral and psychiatric abnormalities such as autism and obsessive-compulsive disorder are also often observed. The movement disorder is prominent and may include cerebellar signs such as ataxia, tremor, dysmetria, poor coordination, and dysarthria. Other abnormal movements including spasticity, myoclonus, and dystonia have been reported, thus widening the phenotypic spectrum. Brain imaging is usually normal, but may show cerebellar atrophy or nonspecific white matter lesions. Variable dysmorphic facial features may also be present.

26. CHARGE syndrome (OMIM 214800)

CHD7 gene (OMIM 608892) on chromosome 8q12; AD

CHARGE syndrome is characterized by a pattern of congenital anomalies including choanal atresia and malformations of the heart, inner ear, and retina.

27. CHILD syndrome (OMIM 308050)

NSDHL gene (OMIM 300275) on chromosome Xq28; XLD

CHILD syndrome is an acronym for an X-linked dominant disorder characterized by congenital hemidysplasia with ichthyosiform erythroderma and limb defects. The mutations are lethal in hemizygous males.

28. Chitayat syndrome; CHYTS (OMIM 617180)

ERF gene (OMIM 611888) on chromosome 19q13; AD

Chitayat syndrome (CHYTS) is a rare condition characterized by respiratory distress presenting at birth, bilateral accessory phalanx resulting in shortened index fingers with ulnar deviation, hallux valgus, and characteristic facial features including prominent eyes, hypertelorism, depressed nasal bridge, full lips, and upturned nose.

29. Chondrodysplasia punctata, X-linked dominant; CDPX2 (OMIM 302960)

EBP gene (OMIM 300205) on chromosome Xp11; XLD

Chondrodysplasia punctata (CDP) is a clinically and genetically heterogeneous disorder characterized by punctiform calcification of the bones. X-linked dominant CDP, also known as Conradi-Hunermann syndrome, is the most well-characterized form. CDPX2 arises almost exclusively in females and is usually lethal in males. In addition to radiographic stippling, the disorder is characterized by rhizomelic shortness, transient congenital ichthyosis following the lines of Blaschko, patchy alopecia, cataracts, and midface hypoplasia. Affected males are extremely rare and the clinical features in males almost always result from postzygotic mosaicism for an EBP mutation.

30. Cleidocranial dysplasia (OMIM 119600)

RUNX2 gene (OMIM 600211) on chromosome 6p21; AD

The main clinical features of cleidocranial dysplasia (CLCD) include persistently open skull sutures with bulging calvaria, hypoplasia or aplasia of the clavicles permitting abnormal facility in apposing the shoulders, wide pubic symphysis, short middle phalanx of the fifth fingers, dental anomalies, and often vertebral malformation.

31. Coffin-Lowry syndrome; CLS (OMIM 303600)

RPS6KA3 gene (OMIM 300075) on chromosome Xp22; XLD

Coffin-Lowry syndrome is a rare form of X-linked mental retardation characterized by skeletal malformations, growth retardation, hearing deficit, paroxysmal movement disorders, and cognitive impairment in affected males and some carrier females.

32. Cognitive impairment with or without cerebellar ataxia; CIAT (OMIM 614306)

SCN8A gene (OMIM 600702) on chromosome 12q13; AD

Cognitive impairment with or without cerebellar ataxia (CIAT) is a disorder characterized by markedly delayed cognitive and motor development, attention deficit disorder, and cerebellar ataxia. Features include bilateral esophoria, strabismatic amblyopia, unsustained gaze evoked nystagmus on horizontal gaze, ataxic gait, dysmetria in the upper limbs and dysarthria, with normal strength, tone, and reflexes. The disease is caused by mutations affecting the gene represented in this entry.

33. Congenital contractures of the limbs and face, hypotonia, and developmental delay; CLIFAHDD (OMIM 616266)

NALCN gene (OMIM 611549) on chromosome 13q33; AD

Congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD) is a congenital disorder characterized by congenital contractures of the limbs and face, resulting in characteristic facial features, hypotonia, and variable degrees of developmental delay. All reported cases have occurred de novo.

34. Cornelia de Lange syndrome; CDLS

The Cornelia de Lange syndrome (CDLS) is a multisystem malformation syndrome recognized primarily on the basis of characteristic facial dysmorphism, including low anterior hairline, arched eyebrows, synophrys, anteverted nares, maxillary prognathism, long philtrum, thin lips, and ‘carp’ mouth, in association with prenatal and postnatal growth retardation, mental retardation and, in many cases, upper limb anomalies. However, there is wide clinical variability in this disorder, with milder phenotypes that may be difficult to ascertain on the basis of physical features.

34.1 Cornelia de Lange syndrome 1; CDLS1 (OMIM 122470)

NIPBL gene (OMIM 608667) on chromosome 5p13; AD

A form of Cornelia de Lange syndrome.

34.2 Cornelia de Lange syndrome 2; CDLS2 (OMIM 300590)

SMC1A gene (OMIM 300040) on chromosome Xp11; XLD

A form of Cornelia de Lange syndrome.

34.3 Cornelia de Lange syndrome 3; CDLS3 (OMIM 610759)

SMC3 gene (OMIM 606062) on chromosome 10q25; AD

A form of Cornelia de Lange syndrome.

34.4 Cornelia de Lange syndrome 4; CDLS4 (OMIM 614701)

RAD21 gene (OMIM 606462) on chromosome 8q24; AD

A form of Cornelia de Lange syndrome.

34.5 Cornelia de Lange syndrome 5; CDLS5 (OMIM 300882)

HDAC8 gene (OMIM 300269) on chromosome Xq13; XLD

A form of Cornelia de Lange syndrome.

35. Cortical dysplasia, complex, with other brain malformations; CECBM

Complex cortical dysplasia with other brain malformations (CDCBM) is a disorder of aberrant neuronal migration and disturbed axonal guidance. Affected individuals have mild to severe mental retardation, strabismus, axial hypotonia, and spasticity. Brain imaging shows variable malformations of cortical development, including polymicrogyria, gyral disorganization, and fusion of the basal ganglia, as well as thin corpus callosum, hypoplastic brainstem, and dysplastic cerebellar vermis. Extraocular muscles are not involved.

35.1 Cortical dysplasia, complex, with other brain malformations 5; CDCBM5 (OMIM 615763)

TUBB2A gene (OMIM 615101) on chromosome 6p25; AD

A form of Complex cortical dysplasia with other brain malformations.

35.2 Cortical dysplasia, complex, with other brain malformations 6; CDCBM6 (OMIM 615763)

TUBB gene (OMIM 191130) on chromosome 6p21; AD

A form of Complex cortical dysplasia with other brain malformations.

36. Costello syndrome; CSTLO (OMIM 218040)

HRAS gene (OMIM 190020) on chromosome 11p15; AD

Costello syndrome is a rare multiple congenital anomaly syndrome associated in all cases with characteristic coarse facies, short stature, distinctive hand posture and appearance, severe feeding difficulty, and failure to thrive. Other features include cardiac anomalies and developmental disability. Facial warts, particularly nasolabial, are often present in childhood.

37. Craniofrontonasal dysplasia; CFNS (OMIM 304110)

EFNB1 gene (OMIM 300035) on chromosome Xq13; XLD

Craniofrontonasal syndrome is an X-linked developmental disorder that shows paradoxically greater severity in heterozygous females than in hemizygous males. Females have frontonasal dysplasia, craniofacial asymmetry, craniosynostosis, bifid nasal tip, grooved nails, wiry hair, and abnormalities of the thoracic skeleton, whereas males typically show only hypertelorism.

38. Craniosynostosis; CRS

Craniosynostosis is a primary abnormality of skull growth involving premature fusion of the cranial sutures such that the growth velocity of the skull often cannot match that of the developing brain. This produces skull deformity and, in some cases, raises intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability.

38.1 Craniosynostosis 1; CRS1 (OMIM 123100)

TWIST1 gene (OMIM 601622) on chromosome 7p21; AD

A form of Craniosynostosis.

38.2 Craniosynostosis 2; CRS2 (OMIM 604757)

MSX2 gene (OMIM 123101) on chromosome 5q35; AD

A form of Craniosynostosis.

38.3 Craniosynostosis 4; CRS4 (OMIM 600775)

ERF gene (OMIM 611888) on chromosome 19q13; AD

A form of Craniosynostosis.

39. Crouzon syndrome (OMIM 123500)

FGFR2 gene (OMIM 176943) on chromosome 10q26; AD

Crouzon syndrome is an autosomal dominant disorder characterized by craniosynostosis causing secondary alterations of the facial bones and facial structure. Common features include hypertelorism, exophthalmos and external strabismus, parrot-beaked nose, short upper lip, hypoplastic maxilla, and a relative mandibular prognathism.

40. Crouzon syndrome with acanthosis nigricans, CAN (OMIM 612247)

FGFR3 gene (OMIM 134934) on chromosome 4p16; AD

Crouzon syndrome with acanthosis nigricans (CAN), also called Crouzonodermoskeletal syndrome, is a disorder characterized by craniosynostosis during development and a skin condition called acanthosis nigricans. The signs and symptoms overlap with those of a similar condition called Crouzon syndrome. Common features include wide-set, bulging eyes, strabismus; a beaked nose; and an underdeveloped upper jaw. Patients are usually of normal intelligence. Acanthosis nigricans is the feature different from Crouzon syndrome. In addition, subtle changes may be seen in the bones of the spine (vertebrae) on Xrays. Noncancerous growths called cementomas may develop in the jaw during young adulthood.

41. Developmental and epileptic encephalopathy 2; DEE2 (OMIM 300672)

CDKL5 gene (OMIM 300203) on chromosome Xp22; XLD

Developmental and epileptic encephalopathy-2 (DEE2) is an X-linked dominant severe neurologic disorder characterized by onset of seizures in the first months of life and severe global developmental delay resulting in impaired intellectual development and poor motor control. Other features include lack of speech development, subtle dysmorphic facial features, sleep disturbances, gastrointestinal problems, and stereotypic hand movements.

42. Developmental and epileptic encephalopathy 4; DEE4 (OMIM 612164)

STXBP1 gene (OMIM 602926) on chromosome 9q34; AD

Developmental and epileptic encephalopathy-4 (DEE4) is a neurologic disorder characterized by the onset of tonic seizures in early infancy (usually in first months of life). In most cases, seizures increase in frequency and become refractory. Affected individuals have profoundly impaired psychomotor development with poor head control, limited or no ability to walk, spastic quadriplegia, and poor or absent speech. Brain imaging may show cortical atrophy and hypomyelination. EEG studies in the more severe cases show a burst-suppression pattern, consistent with a clinical diagnosis of Ohtahara syndrome, and/or hypsarrhythmia, consistent with a clinical diagnosis of West syndrome. Less severely affected individuals have later onset of seizures.

43. Developmental and epileptic encephalopathy 5; DEE5 (OMIM 613477)

SPTAN1 gene (OMIM 182810) on chromosome 9q34; AD

Developmental and epileptic encephalopathy-5 (DEE5) is a neurologic disorder characterized by global developmental delay and the onset of tonic seizures or infantile spasms in the first months of life. The seizures tend to be refractory to treatment, and EEG shows hypsarrhythmia, consistent with a clinical diagnosis of West syndrome. Affected individuals have severely impaired psychomotor development with lack of visual attention, poor head control, feeding difficulties, microcephaly, and spastic quadriplegia. Brain imaging may show cerebral atrophy and hypomyelination.

44. Early Infantile Epileptic Encephalopathy 6 / Dravet syndrome; DEE6A (OMIM 607208)

SCN1A gene (OMIM 182389) on chromosome 2q24; AD

Early Infantile Epileptic Encephalopathy 6 (DEE6A) is a clinical term for a severe neurologic disorder characterized by the onset of seizures in the first year of life after normal early development. Affected individuals usually present with generalized tonic, clonic, and tonic-clonic seizures that may initially be induced by fever and are usually refractory to treatment. Later, patients tend to manifest other seizure types, including absence, myoclonic, and partial seizures. The EEG is often normal at first, but later characteristically shows generalized spike-wave activity and other abnormalities. Psychomotor development stagnates around the second year of life, and affected individuals show subsequent mental decline, behavioral problems, and learning disabilities. ‘Severe myoclonic epilepsy of infancy’ (SMEI) and ‘migrating partial seizures of infancy’ (MPSI) are other clinical manifestations of Dravet syndrome.

45. Developmental and epileptic encephalopathy 6B, non-Dravet; DEE6B (OMIM 619317)

SCN1A gene (OMIM 182389) on chromosome 2q24; AD

Developmental and epileptic encephalopathy-6B (DEE6B) is a severe neurodevelopmental disorder characterized by early-infantile seizure onset, profoundly impaired intellectual development, and a hyperkinetic movement disorder. Brain imaging usually shows progressive atrophy and other abnormalities.

46. Developmental and epileptic encephalopathy 7; DEE7 (OMIM 613720)

KCNQ2 gene (OMIM 602235) on chromosome 20q13; AD

Developmental and epileptic encephalopathy-7 (DEE7) is a neurologic disorder characterized by the onset of refractory seizures in early infancy, often in the neonatal period. Affected individuals have resultant delayed neurologic development and persistent neurologic abnormalities. EEG initially shows a burst suppression pattern, consistent with a clinical diagnosis of Ohtahara syndrome, which may later evolve to multifocal epileptiform activity. Brain imaging in some patients shows lesions in the basal ganglia. Seizures usually remit by age 3 or 4 years, with improvement of EEG abnormalities and possibly brain imaging abnormalities, but the severe neurologic deficits persist.

47. Developmental and epileptic encephalopathy 11; DEE11 (OMIM 613721)

SCN2A gene (182390) on chromosome 2q24; AD

Developmental and epileptic encephalopathy-11 (DEE11) is a neurologic disorder characterized by onset of seizures in the first days, weeks, or months of life. Some patients may have later onset. Seizures comprise multiple types, including tonic, generalized, and myoclonic, and tend to be refractory to medication. However, some patients with onset of seizures before 3 months of age may respond to sodium channel blockers, particularly phenytoin. About half of patients become seizure-free in childhood. Affected individuals have global developmental delay, usually with severely impaired intellectual development, although some may be less severely affected and show autism spectrum disorder. Additional common features include microcephaly, hypotonia, and abnormal movements, such as dystonia, dyskinesias, and choreoathetotic movements. Brain imaging may show white matter defects. The phenotype is highly variable, even in patients with the same mutation.

48. Developmental and epileptic encephalopathy 13; DEE13 (OMIM 614558)

SCN8A gene (600702) on chromosome 12q13; AD

Developmental and epileptic encephalopathy-13 (DEE13) is a neurologic disorder characterized by the onset of intractable seizures in the first year of life. Some patients may present with seizures in the first days, whereas others present later (between 2 and 7 months of age) after normal or only mild developmental delay. Affected individuals have profoundly impaired development or developmental regression after the onset of seizures, and show severe intellectual disability, poor or absent language, hypotonia, and are usually unable to walk. EEG shows variable abnormalities, including multifocal and generalized spike-wave discharges, sometimes with status epilepticus or hypsarrhythmia. Brain imaging may show cerebral atrophy.

49. Developmental and epileptic encephalopathy 14; DEE14 (OMIM 614959)

KCNT1 gene (608167) on chromosome 9q34; AD

Developmental and epileptic encephalopathy-14 (DEE14) is a severe neurologic disorder characterized by onset in the first 6 months of life of refractory focal seizures and arrest of psychomotor development. Ictal EEG shows discharges that arise randomly from various areas of both hemispheres and migrate from one brain region to another. The disorder presents as ‘malignant migrating partial seizures of infancy’ (MMPSI), a clinical designation.

50. Developmental and epileptic encephalopathy 17; DEE17 (OMIM 615473)

GNAO1 gene (139311) on chromosome 16q13; AD

Developmental and epileptic encephalopathy-17 (DEE17) is a severe neurologic disorder characterized by onset of intractable seizures in the first weeks or months of life. EEG often shows a burst-suppression pattern consistent with a clinical diagnosis of Ohtahara syndrome. Affected infants have very poor psychomotor development and may have brain abnormalities, such as cerebral atrophy or thin corpus callosum. Some patients may show involuntary movements.

51. Developmental and epileptic encephalopathy 19; DEE19 (OMIM 615744)

GABRA1 gene (OMIM 137160) on chromosome 5q34; AD

Developmental and epileptic encephalopathy-19 (DEE19) is a neurologic disorder characterized by the onset of various types of seizures in the first year of life, usually between 8 and 12 months of age. Seizures are often triggered by fever, and status epilepticus may occur. Affected individuals subsequently show mildly to moderately impaired intellectual development. Brain imaging is typically normal. The clinical phenotype is similar to that of Dravet syndrome.

52. Developmental and epileptic encephalopathy 26; DEE26 (OMIM 616056)

KCNB1 gene (OMIM 600397) on chromosome 20q13; AD

Developmental and epileptic encephalopathy-26 (DEE26) is a neurologic disorder characterized by onset of variable types of seizures late in infancy or in the first years of life. Affected children show developmental delay with intellectual disability, poor speech, and behavioral abnormalities. EEG shows multifocal epileptic discharges, and may show hypsarrhythmia.

53. Developmental and epileptic encephalopathy 27; DEE27 (OMIM 616139)

GRIN2B gene (OMIM 138252) on chromosome 12p12; AD

Developmental and epileptic encephalopathy-27 (DEE27) is an autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development and intellectual disability of variable severity associated with early-onset seizures. Additional features may include hypotonia, abnormal movements, such as dystonia, and autistic features. Some patients may have structural malformations of cortical development on brain imaging. The phenotype is highly variable and reflects a spectrum of neurodevelopmental abnormalities that range from mild intellectual disability without seizures to an encephalopathy.

54. Developmental and epileptic encephalopathy 31A; DEE31A (OMIM 616346)

DNM1 gene (OMIM 602377) on chromosome 9q34; AD

Developmental and epileptic encephalopathy-31A (DEE31A) is an autosomal dominant neurologic disorder characterized by the global developmental delay apparent in early infancy. Most individuals have onset of various types of refractory seizures in the first months or years of life, which exacerbates the psychomotor deficits. Patients have hypotonia and profound intellectual disability with absent speech and inability to walk or ataxic gait. Some patients may have additional features, including dysmorphic features or cortical visual impairment.

55. Developmental and epileptic encephalopathy 42; DEE42 (OMIM 617106)

CACNA1A gene (OMIM 601011) on chromosome 19p13; AD

Developmental and epileptic encephalopathy-42 (DEE42) is a neurologic disorder characterized by the onset of various types of seizures in the first hours or days of life, although rare patients may have onset in the first weeks of life. The seizures tend to be refractory and associated with EEG abnormalities, including multifocal spikes and generalized spike-wave complexes. Affected infants show global developmental delay with severely impaired intellectual development. Other features may include axial hypotonia, peripheral hypertonia with hyperreflexia, tremor, ataxia, and abnormal eye movements.

56. Developmental and epileptic encephalopathy 54; DEE54 (OMIM 617391)

HNRNPU gene (OMIM 602869) on chromosome 1q44; AD

Developmental and epileptic encephalopathy-54 (DEE54) is a severe neurodevelopmental disorder characterized by delayed psychomotor development, early-onset refractory seizures that are often initially febrile but later afebrile, and severe intellectual disability.

57. Developmental and epileptic encephalopathy 92; DEE92 (OMIM 617829)

GABRB2 gene (OMIM 600232) on chromosome 5q34; AD

Developmental and epileptic encephalopathy-92 (DEE92) is characterized in most patients by onset of seizures in infancy or childhood and associated with global developmental delay and variable impairment of intellectual development. The seizure type and severity varies, and seizures may be intractable in some patients. Some patients are severely affected, unable to walk or speak, whereas others show some development. Additional neurologic features, including cortical blindness, dystonia, and spasticity, may occur.

58. Developmental and epileptic encephalopathy 94; DEE94 (OMIM 615369)

CHD2 gene (OMIM 602119) on chromosome 15q26; AD

Developmental and epileptic encephalopathy-94 (DEE94) is a severe form of epilepsy characterized by onset of multiple seizure types in the first few years of life and associated with poor prognosis. Affected individuals have cognitive regression and impaired intellectual development.

59. Developmental and epileptic encephalopathy 98; DEE98 (OMIM 619605)

ATP1A2 gene (OMIM 182340) on chromosome 1q23; AD

Developmental and epileptic encephalopathy-98 (DEE98) is characterized by onset of seizures in the first decade (range infancy to late childhood) associated with variable global developmental delay. Other features may include hypotonia, spasticity, and quadriparesis. Brain imaging may be normal or show nonspecific and variable abnormalities, including polymicrogyria. The severity is variable; some patients may die of refractory status epilepticus.

60. Developmental and epileptic encephalopathy 99; DEE99 (OMIM 619606)

ATP1A3 gene (OMIM 182350) on chromosome 19q13; AD

Developmental and epileptic encephalopathy-99 (DEE99) is characterized by onset of seizures in early childhood associated with global developmental delay and severely impaired intellectual development. Other features may include hypotonia, quadriparesis, nystagmus, and apnea. Brain imaging may be normal or show nonspecific and variable abnormalities, including cerebral atrophy and polymicrogyria. The severity is variable; some patients die of refractory status epilepticus.

61. Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities; DEHMBA (OMIM 619595)

SRCAP gene (611421) on chromosome 16p11; AD

Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities (DEHMBA) is an early-onset neurodevelopmental disorder characterized by these features. Affected individuals also have nonspecific and variable dysmorphic facial features that do not constitute a recognizable gestalt. Although the disorder is caused by truncating mutations in the SRCAP gene as is FLHS, the DEHMBA phenotype is clinically distinguishable from FLHS by the lack of short stature, brachydactyly, and delayed bone age, as well as absence of a specific facial appearance. There are some overlapping features between the 2 disorders, mainly impaired intellectual development and speech delay.

62. Dias-Logan syndrome (OMIM 617101)

BCL11A gene (606557) on chromosome 2p16.

Intellectual developmental disorder with persistence of fetal hemoglobin (Dias-Logan syndrome) is characterized by delayed psychomotor development, intellectual disability, variable dysmorphic features, including microcephaly, downslanting palpebral fissures, strabismus, and external ear abnormalities, and asymptomatic persistence of fetal hemoglobin (HbF).

63. Epiphyseal dysplasia, multiple, 1; EDM1 (OMIM 132400)

COMP gene (OMIM 600310) on chromosome 19p13; AD

Multiple epiphyseal dysplasia is a skeletal disorder characterized by short stature and early-onset osteoarthrosis.

64. Epiphyseal dysplasia, multiple, 2; EDM2 (OMIM 600204)

COL9A2 gene (OMIM 120260) on chromosome 1p34; AD

Multiple epiphyseal dysplasia is a clinically and genetically heterogeneous skeletal disorder characterized by joint pain and stiffness, mild short stature, and degenerative joint disease. Onset of the disorder is usually in childhood.

65. Epiphyseal dysplasia, multiple, 3, with or without myopathy; EDM3 (OMIM 600969)

COL9A3 gene (OMIM 120270) on chromosome 20q13; AD

Multiple epiphyseal dysplasia is characterized by early-onset short stature, waddling gait, and stiffness and/or pain in the knees and sometimes other joints.

66. Episodic ataxia, type 9; EA9 (OMIM 618924)

SCN2A gene (OMIM 182390) on chromosome 2q23; AD

Episodic ataxia type 9 (EA9) is a neurologic disorder characterized by onset of ataxic episodes in the first years of life. Features may include difficulty walking, dizziness, slurred speech, headache, vomiting, and pain. The ataxic episodes vary in frequency and duration; most tend to occur every few weeks or months and last minutes to hours. Prior to the EA, most patients have neonatal- or infantile-onset tonic or generalized tonic-clonic (GTC) seizures that may be severe and refractory to medication, but remit later in infancy or early childhood, either spontaneously or concurrently with medication. Some patients have mildly delayed development with speech delay and/or autistic features or mildly impaired intellectual development. However, others show normal psychomotor development. Treatment of the ataxic episodes with acetazolamide is effective in about 50% of patients.

67. Fibrodysplasia ossificans progressiva; FOP (OMIM 135100)

ACVR1 gene (OMIM 102576) on chromosome 2q24; AD

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disease with complete penetrance involving progressive ossification of skeletal muscle, fascia, tendons, and ligaments. FOP has a prevalence of approximately 1 in 2 million worldwide, and shows no geographic, ethnic, racial, or gender preference. Individuals with FOP appear normal at birth except for great toe abnormalities: the great toes are short, deviated, and monophalangic. Ossification occurs progressively over the course of a lifetime in an inevitable and unpredictable episodic manner, with most patients being confined to a wheelchair by the third decade of life and requiring lifelong care.

68. Floating-Harbor syndrome; FLHS/FHS (OMIM 136140)

SRCAP gene (OMIM 611421) on chromosome 16p11; AD

Floating-Harbor syndrome (FLHS) is a rare genetic disorder characterized by proportionate short stature, delayed bone age, delayed speech development, and typical facial features. The face is triangular with deep-set eyes, long eyelashes, bulbous nose, wide columella, short philtrum, and thin lips.

69. Fontaine progeroid syndrome; FPS (OMIM 612289)

SLC25A24 gene (OMIM 608744) on chromosome 1p36; AD

Fontaine progeroid syndrome (FPS) is characterized by prenatal and postnatal growth retardation, decreased subcutaneous fat tissue, sparse hair, triangular face, widely open anterior fontanel, convex and broad nasal ridge, micrognathia, craniosynostosis in some patients, and early death in many.

70. GAND syndrome; GAND (OMIM 615074)

GATAD2B gene (OMIM 614998) on chromosome 1q21; AD

GAND syndrome is a neurodevelopmental syndrome characterized by global developmental delay apparent from infancy, with motor delay and moderate to severely impaired intellectual development. Most patients have poor speech acquisition, especially expressive language development, and may manifest signs of speech apraxia. Affected individuals have hypotonia and feeding difficulties in infancy, as well as common dysmorphic features, such as macrocephaly, frontal bossing, hypertelorism, deep-set eyes, posteriorly rotated ears, and elongated wide nose with prominent nasal tip. More variable features may include seizures, cardiac abnormalities, and nonspecific findings on brain imaging.

71. Genitopatellar syndrome; GTPTS (OMIM 606170)

KAT6B gene (OMIM 605880) on chromosome 10q22; AD

Genitopatellar syndrome is a rare disorder consisting of microcephaly, severe psychomotor retardation, and characteristic coarse facial features, including broad nose and small or retracted chin, associated with congenital flexion contractures of the lower extremities, abnormal or missing patellae, and urogenital anomalies.

72. Glass syndrome; GLASS (OMIM 612313)

SATB2 gene (608148) on chromosome 2q33; AD

Glass syndrome (GLASS) is characterized by intellectual disability of variable severity and dysmorphic facial features, including micrognathia, downslanting palpebral fissures, cleft palate, and crowded teeth. Additional features may include seizures, joint laxity, arachnodactyly, and happy demeanor.

73. Hajdu-Cheney syndrome; HJCYS (OMIM 102500)

NOTCH2 gene (600275) on chromosome 1p12; AD

Hajdu-Cheney syndrome (HJCYS) is a rare autosomal dominant skeletal disorder characterized by short stature, coarse and dysmorphic facies, bowing of the long bones, and vertebral anomalies. Facial features include hypertelorism, bushy eyebrows, micrognathia, small mouth with dental anomalies, lowset ears, and short neck. There is progressive focal bone destruction, including acroosteolysis and generalized osteoporosis. Additional and variable features include hearing loss, renal cysts, and cardiovascular anomalies.

74. Holt-Oram syndrome; HOS (OMIM 142900)

TBX5 gene (OMIM 601620) on chromosome 12q24; AD

Holt-Oram syndrome is an autosomal dominant disorder characterized by abnormalities of the upper limbs and shoulder girdle, associated with a congenital heart lesion. The typical combination is considered to be a triphalangeal thumb with a secundum atrial septal defect (ASD), but there is a great range in the severity of both the heart and skeletal lesions.

75. Hutchinson-Gilford progeria syndrome; HGPS (OMIM 176670)

LMNA (OMIM 150330) on chromosome 1q22; AD

Hutchinson-Gilford progeria syndrome is a rare disorder characterized by short stature, low body weight, early loss of hair, lipodystrophy, scleroderma, decreased joint mobility, osteolysis, and facial features that resemble aged persons. Cardiovascular compromise leads to early death. Cognitive development is normal. Onset is usually within the first year of life.

76. Hyper-IgE recurrent infection syndrome / Hyper-IgE syndrome-1 with recurrent infections; HIES1 (OMIM 147060)

STAT3 gene (OMIM 102582) on chromosome 17q21; AD

Hyper-IgE syndrome-1 with recurrent infections (HIES1) is an autosomal dominant immunologic disorder characterized by chronic eczema (atopy), recurrent Staphylococcal infections, increased serum IgE, and eosinophilia. Other more variable immunologic abnormalities include defective granulocyte chemotaxis, abnormalities in T-lymphocyte subgroups, impaired antibody production, and decreased production of or response to certain cytokines. Importantly, the same immune system defects are not found in all patients. Some patients may have a distinctive coarse facial appearance, abnormal dentition, hyperextensibility of the joints, and bone fractures.

77. Hypochondroplasia; HCH (OMIM 146000)

FGFR3 gene (OMIM 134934) on chromosome 4p16; AD

Hypochondroplasia (HCH) is an autosomal dominant disorder characterized by short-limbed dwarfism, lumbar lordosis, short and broad bones, and caudad narrowing of the interpediculate distance of the lumbar spine. It shows some resemblance to achondroplasia, but is much milder and can be distinguished on clinical and radiographic grounds.

78. Impaired intellectual development and distinctive facial features with or without cardiac defects; MRFACD (OMIM 616789)

MED13L gene (OMIM 608771) on chromosome 12q24; AD

Impaired intellectual development and distinctive facial features with or without cardiac defects (MRFACD) is an autosomal dominant, complex syndromic neurodevelopmental disorder characterized by delayed psychomotor development, poor speech acquisition, distinctive dysmorphic facial features, including frontal bossing, upslanting palpebral fissures, depressed nasal bridge with bulbous tip, and macrostomia. There is variable penetrance of cardiac malformations, ranging from no malformations to patent foramen ovale to septal defects and/or transposition of the great arteries.

79. Intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia; MICPCH (OMIM 300749)

CASK gene (OMIM 300172) on chromosome Xp11; XLD

Intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH) is an X-linked disorder affecting males and females. In females, it is characterized by severely impaired intellectual development and variable degrees of pontocerebellar hypoplasia. Affected females have poor psychomotor development, often without independent ambulation or speech, and axial hypotonia with or without hypertonia. Some may have sensorineural hearing loss, eye anomalies, or seizures. Dysmorphic features include overall poor growth, severe microcephaly (-3.5 to -10 SD), broad nasal bridge and tip, large ears, long philtrum, micrognathia, and hypertelorism. Like females with MICPCH, affected males have microcephaly that is congenital or evolves rapidly during the first few months of life. MRI findings show significant or severe pontocerebellar hypoplasia. MICPCH in males may occur with or without severe epileptic encephalopathy in addition to severe to profound developmental delay. When seizures are present, they occur early and may be intractable. A few males have been noted to have MICPCH and severe developmental delay but without severe epilepsy.

80. Intellectual developmental disorder with autism and macrocephaly; IDDAM (OMIM 615032)

CHD8 gene (OMIM 610528) on chromosome 14q11; AD

Intellectual developmental disorder with autism and macrocephaly (IDDAM) is characterized by impaired intellectual development, a highly penetrant autism spectrum phenotype, and macrocephaly. Other common features include tall stature, gastrointestinal symptoms, distinct facial features, sleep problems, and attention problems.

81. Intellectual developmental disorder with language impairment with or without autistic features (OMIM 613670)

FOXP1 gene (OMIM 605515) on chromosome 3p13; AD

Intellectual developmental disorder with language impairment and with or without autistic features is a neurodevelopmental disorder characterized by global developmental delay with moderate to severe speech delay that particularly affects expressive speech. Most patients have articulation defects, but frank verbal dyspraxia is not observed. Common dysmorphic features include broad forehead, downslanting palpebral fissures, short nose with broad tip, relative macrocephaly, frontal hair upsweep, and prominent digit pads. Gross motor skills are also delayed. Some patients have autistic features and/or behavioral problems. All reported cases have occurred de novo.

82. Intellectual developmental disorder, autosomal dominant; MRD

Intellectual developmental disorder, autosomal dominant (MRD) is an autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development and intellectual disability of variable severity.