GRIN2A-related speech disorders and epilepsy are characterized by speech disorders in all affected individuals and a range of epilepsy syndromes present in about 90%. Severe speech disorders observed can include dysarthria and speech dyspraxia, and both receptive and expressive language delay/regression; more mildly affected individuals may display subtly impaired intelligibility of conversational speech. Epilepsy features include seizure onset usually between ages three and six years, focal epilepsy with language and/or global developmental regression, and electroencephalogram (EEG) showing continuous spike-and-wave discharges in sleep or very active centrotemporal discharges. Seizure types include seizures associated with aura of perioral paresthesia, focal or focal motor seizures (often evolving to generalized tonic-clonic), and atypical absence seizures. Epilepsy syndromes can include: Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), childhood epilepsy with centrotemporal spikes (CECTS), atypical childhood epilepsy with centrotemporal spikes (ACECTS), autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD), and infantile-onset epileptic encephalopathy.

Jawad syndrome (JWDS) is an autosomal recessive disorder characterized by congenital microcephaly, moderate to severely impaired intellectual development, and digital malformations including phalangeal joint swelling, clinodactyly, polydactyly, syndactyly, and total absence of nails (summary by Qvist et al., 2011).

Amish lethal microcephaly is characterized by severe congenital microcephaly and highly elevated 2-ketoglutarate or lactic acidosis. The occipitofrontal circumference is typically more than two standard deviations (occasionally >6 SD) below the mean; anterior and posterior fontanels are closed at birth and facial features are distorted. The average life span of an affected infant is between five and six months among the Lancaster Amish, although an affected Amish-Mennonite child was reported to be living with severe developmental delay at age seven years.

Seckel syndrome is a rare autosomal recessive disorder characterized by growth retardation, microcephaly with mental retardation, and a characteristic facial appearance (Borglum et al., 2001). For a general phenotypic description and a discussion of genetic heterogeneity of Seckel syndrome, see SCKL1 (210600).

Cornelia de Lange syndrome (CdLS) encompasses a spectrum of findings from mild to severe. Severe (classic) CdLS is characterized by distinctive facial features, growth restriction (prenatal onset; <5th centile throughout life), hypertrichosis, and upper-limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly (missing digits). Craniofacial features include synophrys, highly arched and/or thick eyebrows, long eyelashes, short nasal bridge with anteverted nares, small widely spaced teeth, and microcephaly. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement, but often have facial features consistent with CdLS. Across the CdLS spectrum IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Other frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia.

Primary microcephaly refers to the clinical finding of a head circumference more than than 3 standard deviations (SD) below the age- and sex-related mean, present at birth. Primary microcephaly is a static developmental anomaly, distinguished from secondary microcephaly, which refers to a progressive neurodegenerative condition. Microcephaly is a disorder of fetal brain growth; individuals with microcephaly have small brains and almost always have mental retardation, although rare individuals with mild microcephaly (-3 SD) and normal intelligence have been reported. Additional clinical features may include short stature or mild seizures. MCPH is associated with a simplification of the cerebral cortical gyral pattern and a slight reduction in the volume of the white matter, consistent with the small size of the brain, but the architecture of the brain in general is normal, with no evidence of a neuronal migration defect (review by Woods et al., 2005). Most cases of primary microcephaly show an autosomal recessive mode of inheritance. Because MCPH directly affects neurogenesis, or neurogenic mitosis, rather than growth of the skull, some prefer the term 'micrencephaly' (Hofman, 1984). MCPH1 in particular is associated with premature chromosome condensation in cell studies (Darvish et al., 2010). Genetic Heterogeneity of Primary Microcephaly Primary microcephaly is a genetically heterogeneous disorder. See MCPH2 (604317), caused by mutation in the WDR62 gene (613583) on chromosome 19q13; MCPH3 (604804), caused by mutation in the CDK5RAP2 gene (608201) on 9q33; MCPH4 (604321), caused by mutation in the CASC5 gene (609173) on 15q14; MCPH5 (608716), caused by mutation in the ASPM gene (605481) on 1q31; MCPH6 (608393), caused by mutation in the CENPJ gene (609279) on 13q12; MCPH7 (612703), caused by mutation in the STIL gene (181590) on 1p33; MCPH8 (614673), caused by mutation in the CEP135 gene (611423) on 4q12; MCPH9 (614852), caused by mutation in the CEP152 gene (613529) on 15q21; MCPH10 (615095), caused by mutation in the ZNF335 gene (610827) on 20q13; MCPH11 (615414), caused by mutation in the PHC1 gene (602978) on 12p13; MCPH12 (616080), caused by mutation in the CDK6 gene (603368) on 7q21; MCPH13 (616051), caused by mutation in the CENPE gene (117143) on 4q24; MCPH14 (616402), caused by mutation in the SASS6 gene (609321) on 1p21; MCPH15 (616486), caused by mutation in the MFSD2A gene (614397) on 1p34; MCPH16 (616681), caused by mutation in the ANKLE2 gene (616062) on 12q24; MCPH17 (617090), caused by mutation in the CIT gene (605629) on 12q24; MCPH18 (617520), caused by mutation in the WDFY3 gene (617485) on 4q21; MCPH19 (617800), caused by mutation in the COPB2 gene (606990) on 3q23; MCPH20 (617914), caused by mutation in the KIF14 gene (611279) on 1q31; MCPH21 (617983), caused by mutation in the NCAPD2 gene (615638) on 12p13; MCPH22 (617984), caused by mutation in the NCAPD3 gene (609276) on 11q25; MCPH23 (617985), caused by mutation in the NCAPH gene (602332) on 2q11; MCPH24 (618179), caused by mutation in the NUP37 gene (609264) on 12q23; MCPH25 (618351), caused by mutation in the MAP11 gene (618350) on 7q22; MCPH26 (619179), caused by mutation in the LMNB1 gene (150340) on 5q23; MCPH27 (619180), caused by mutation in the LMNB2 gene (150341) on 19p13; MCPH28 (619453), caused by mutation in the RRP7A gene (619449) on 22q13; MCPH29 (620047), caused by mutation in the PDCD6IP gene (608074) on 3p22; and MCPH30 (620183), caused by mutation in the BUB1 gene (602452) on 2q14.

People with MCPH usually have few or no other features associated with the condition. Some have a narrow, sloping forehead; mild seizures; problems with attention or behavior; or short stature compared to others in their family. The condition typically does not affect any other major organ systems or cause other health problems.\n\nInfants with MCPH have an unusually small head circumference compared to other infants of the same sex and age. Head circumference is the distance around the widest part of the head, measured by placing a measuring tape above the eyebrows and ears and around the back of the head. Affected infants' brain volume is also smaller than usual, although they usually do not have any major abnormalities in the structure of the brain. The head and brain grow throughout childhood and adolescence, but they continue to be much smaller than normal.\n\nMCPH causes intellectual disability, which is typically mild to moderate and does not become more severe with age. Most affected individuals have delayed speech and language skills. Motor skills, such as sitting, standing, and walking, may also be mildly delayed.\n\nAutosomal recessive primary microcephaly (often shortened to MCPH, which stands for "microcephaly primary hereditary") is a condition in which infants are born with a very small head and a small brain. The term "microcephaly" comes from the Greek words for "small head."

Primary microcephaly (MCPH) is a clinical diagnosis made when an individual has a head circumference more than 3 standard deviations below the age- and sex-matched population mean and mental retardation, with no other associated malformations and with no apparent etiology. Most cases of primary microcephaly show an autosomal recessive mode of inheritance (summary by Woods et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).

Phosphoglycerate dehydrogenase deficiency (PHGDHD) is an autosomal recessive inborn error of L-serine biosynthesis that is characterized by congenital microcephaly, psychomotor retardation, and seizures (summary by Jaeken et al., 1996).

Autosomal recessive primary microcephaly (often shortened to MCPH, which stands for "microcephaly primary hereditary") is a condition in which infants are born with a very small head and a small brain. The term "microcephaly" comes from the Greek words for "small head."\n\nMCPH causes intellectual disability, which is typically mild to moderate and does not become more severe with age. Most affected individuals have delayed speech and language skills. Motor skills, such as sitting, standing, and walking, may also be mildly delayed.\n\nInfants with MCPH have an unusually small head circumference compared to other infants of the same sex and age. Head circumference is the distance around the widest part of the head, measured by placing a measuring tape above the eyebrows and ears and around the back of the head. Affected infants' brain volume is also smaller than usual, although they usually do not have any major abnormalities in the structure of the brain. The head and brain grow throughout childhood and adolescence, but they continue to be much smaller than normal.\n\nPeople with MCPH usually have few or no other features associated with the condition. Some have a narrow, sloping forehead; mild seizures; problems with attention or behavior; or short stature compared to others in their family. The condition typically does not affect any other major organ systems or cause other health problems.

Developmental and epileptic encephalopathy-39 with leukodystrophy (DEE39) is an autosomal recessive neurologic syndrome characterized clinically by global developmental delay apparent in early infancy, early-onset seizures, hypotonia with poor motor function, and hypomyelination on brain imaging. Other features include absent speech and inability to walk; spasticity and hyperreflexia has also been reported. Although there is significant hypomyelination on brain imaging, the disorder was not classified as a primary leukodystrophy. The myelination defect was thought to stem from primary neuronal dysfunction due to impaired mitochondrial transport activity (summary by Wibom et al., 2009 and Falk et al., 2014). However, serial brain imaging in a patient with DEE39 by Kavanaugh et al. (2019) suggested that the mechanism of disease is consistent with a leukoaxonopathy type of leukodystrophy. For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

CDG IIe is caused by a mutation that impairs the integrity of the conserved oligomeric Golgi (COG) complex and alters Golgi trafficking, resulting in the disruption of multiple glycosylation pathways. For a general discussion of CDGs, see CDG1A (212065).

The cardinal features of chromosome 6q11-q14 interstitial deletions include hypotonia, short stature, skeletal/limb anomalies, umbilical hernia, and urinary tract anomalies, as well as characteristic facial features including upslanting palpebral fissures, low-set and/or dysplastic ears, and high-arched palate (summary by Wang et al., 2009).

Lissencephaly-4 with microcephaly (LIS4) is an autosomal recessive neurodevelopmental disorder characterized by lissencephaly, severe brain atrophy, extreme microcephaly (head circumference of more than 10 standard deviations (SD) below the mean), and profoundly impaired intellectual development. It has also been referred to as 'microlissencephaly' (summary by Bakircioglu et al., 2011 and Alkuraya et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of lissencephaly, see LIS1 (607432).

Primary microcephaly-epilepsy-permanent neonatal diabetes syndrome is a rare, genetic, neurologic disease characterized by congenital microcephaly, severe, early-onset epileptic encephalopathy (manifesting as intractable, myoclonic and/or tonic-clonic seizures), permanent, neonatal, insulin-dependent diabetes mellitus, and severe global developmental delay. Muscular hypotonia, skeletal abnormalities, feeding difficulties, and dysmorphic facial features (including narrow forehead, anteverted nares, small mouth with deep philtrum, tented upper lip vermilion) are frequently associated. Brain MRI reveals cerebral atrophy with cortical gyral simplification and aplasia/hypoplasia of the corpus callosum.

Any autosomal recessive primary microcephaly in which the cause of the disease is a mutation in the CEP135 gene.

Any Seckel syndrome in which the cause of the disease is a mutation in the CEP63 gene.

CTNNB1 neurodevelopmental disorder (CTNNB1-NDD) is characterized in all individuals by mild-to-profound cognitive impairment and in up to 39% of reported individuals by exudative vitreoretinopathy, an ophthalmologic finding consistent with familial exudative vitreoretinopathy (FEVR). Other common findings include truncal hypotonia, peripheral spasticity, dystonia, behavior problems, microcephaly, and refractive errors and strabismus. Less common features include intrauterine growth restriction, feeding difficulties, and scoliosis.

Primary microcephaly-10 (MCPH10) is an autosomal recessive disorder characterized by extremely small head size (-9 SD) at birth and death usually by 1 year of age. Neuropathologic examination shows severe loss of neurons as well as neuronal loss of polarity and abnormal dendritic maturation (summary by Yang et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).

Asparagine synthetase deficiency (ASD) mainly presents as a triad of congenital microcephaly, severe developmental delay, and axial hypotonia followed by spastic quadriplegia. Low cerebrospinal fluid (CSF) asparagine level can help the clinician in differentiating this disorder from others. In most cases age of onset of apnea, excessive irritability, and seizures is soon after birth. Affected individuals typically do not acquire any developmental milestones. Spastic quadriplegia can lead to severe contractures of the limbs and neurogenic scoliosis. Feeding difficulties (gastroesophageal reflux disease, frequent vomiting, swallowing dysfunction, and gastroesophageal incoordination) are a significant problem in most affected individuals. A majority have cortical blindness. MRI findings are nonspecific but may include generalized atrophy and simplified gyral pattern.

Most characteristically, Aicardi-Goutières syndrome (AGS) manifests as an early-onset encephalopathy that usually, but not always, results in severe intellectual and physical disability. A subgroup of infants with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia, a picture highly suggestive of congenital infection. Otherwise, most affected infants present at variable times after the first few weeks of life, frequently after a period of apparently normal development. Typically, they demonstrate the subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. Over time, as many as 40% develop chilblain skin lesions on the fingers, toes, and ears. It is becoming apparent that atypical, sometimes milder, cases of AGS exist, and thus the true extent of the phenotype associated with pathogenic variants in the AGS-related genes is not yet known.

Any complex cortical dysplasia with other brain malformations in which the cause of the disease is a mutation in the TUBB gene.

Microcephaly, short stature, and impaired glucose metabolism-1 (MSSGM1) is an autosomal recessive syndrome characterized by microcephaly associated with impaired intellectual development, short stature, and early-onset diabetes or abnormalities of glucose homeostasis (Igoillo-Esteve et al., 2013; Gillis et al., 2014). Genetic Heterogeneity of Microcephaly, Short Stature, and Impaired Glucose Metabolism MSSGM2 (616817) is caused by mutation in the PPP1R15B gene (613257) on chromosome 1q32. Also see Wolcott-Rallison syndrome (226980), which is characterized by multiple epiphyseal dysplasia, microcephaly, short stature, and early-onset diabetes mellitus and is caused by mutation in the EIF2AK3 gene (604032) on chromosome 2p11.

Any autosomal recessive primary microcephaly in which the cause of the disease is a mutation in the CENPE gene.

Any autosomal recessive primary microcephaly in which the cause of the disease is a mutation in the CDK6 gene.

A rare genetic neurological disorder with characteristics of congenital microcephaly, severe intellectual disability, hypertonia at birth lessening with age, ataxia and specific dysmorphic facial features including hirsutism, low anterior hairline and bitemporal narrowing arched thick and medially sparse eyebrows, long eyelashes, lateral upper eyelids swelling and a skin fold partially covering the inferior eyelids, low-set posteriorly rotated protruding ears, anteverted nares and a full lower lip. Brain imaging shows partial to almost complete agenesis of the corpus callosum and variable degrees of cerebellar hypoplasia. Caused by homozygous mutation in the FRMD4A gene on chromosome 10p13.

Any autosomal recessive primary microcephaly in which the cause of the disease is a mutation in the SASS6 gene.

Arboleda-Tham syndrome (ARTHS) is an autosomal dominant disorder with the core features of impaired intellectual development, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications (summary by Kennedy et al., 2019).

GRIDHH is an autosomal recessive multisystem disorder characterized by poor overall growth, impaired intellectual development, hypotonia, and variable liver dysfunction. Additional features, such as seizures and hearing loss, may also be present (summary by Kopajtich et al., 2016).

Autosomal recessive primary microcephaly-17 (MCPH17) is a severe neurologic disorder characterized by very small head circumference that is apparent at birth and worsens over time (up to -12 SD). Affected individuals have delayed psychomotor development, intellectual disability, spasticity, axial hypotonia, and dysmorphic features. Brain imaging shows a simplified gyral pattern; more severe cases have lissencephaly with hypoplasia of the brainstem and cerebellum (summary by Harding et al., 2016). For a phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).

Neurodevelopmental disorder with midbrain and hindbrain malformations (NEDMHM) is an autosomal recessive disorder comprising impaired intellectual development, speech delay, mild microcephaly, and midbrain-hindbrain malformation (Ravindran et al., 2017).

Diencephalic-mesencephalic junction dysplasia syndrome-1 (DMJDS1) is an autosomal recessive neurodevelopmental disorder characterized by progressive microcephaly, severely delayed or even absent psychomotor development with profound intellectual disability, and spasticity or dystonia. Some patients may have seizures and/or visual impairment. Brain imaging shows a characteristic developmental malformation of the midbrain; subtle intracranial calcifications may also be present (summary by Aran et al., 2016 and Guemez-Gamboa et al., 2018). Genetic Heterogeneity of Diencephalic-Mesencephalic Junction Dysplasia Syndrome See also DMJDS2 (618646), caused by mutation in the GSX2 gene (616253) on chromosome 4q12.

Galloway-Mowat syndrome is a renal-neurologic disease characterized by early-onset nephrotic syndrome associated with microcephaly, gyral abnormalities of the brain, and delayed psychomotor development. Most patients have dysmorphic facial features, often including hypertelorism, ear abnormalities, and micrognathia. Other features, such as arachnodactyly and visual impairment, are more variable. Most patients die in the first years of life (summary by Braun et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of GAMOS, see GAMOS1 (251300).

Galloway-Mowat syndrome is a renal-neurologic disease characterized by early-onset nephrotic syndrome associated with microcephaly, gyral abnormalities, and delayed psychomotor development. Most patients have dysmorphic facial features, often including hypertelorism, ear abnormalities, and micrognathia. Other features, such as arachnodactyly and visual impairment, are more variable. Most patients die in the first years of life (summary by Braun et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of GAMOS, see GAMOS1 (251300).

Galloway-Mowat syndrome is a renal-neurologic disease characterized by early-onset nephrotic syndrome associated with microcephaly, gyral abnormalities, and delayed psychomotor development. Most patients have dysmorphic facial features, often including hypertelorism and ear abnormalities. Other features, such as arachnodactyly and visual or hearing impairment, are more variable. Most patients die in the first years of life (summary by Braun et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of GAMOS, see GAMOS1 (251300).

Any Neu-Laxova syndrome in which the cause of the disease is a mutation in the PHGDH gene.

Sandestig-Stefanova syndrome (SANDSTEF) is an autosomal recessive developmental syndrome characterized by pre- and postnatal microcephaly, trigonocephaly, congenital cataract, microphthalmia, facial gestalt, camptodactyly, loss of periventricular white matter, thin corpus callosum, delayed myelinization, and poor prognosis (Sandestig et al., 2019).

Nabais Sa-de Vries syndrome type 1 (NSDVS1) is characterized by global developmental delay apparent from infancy, variable behavioral abnormalities, microcephaly, and dysmorphic facial features, including round face, small palpebral fissures, highly arched eyebrows, and short nose. The severity is variable (summary by Nabais Sa et al., 2020).

Autosomal dominant primary microcephaly-27 (MCPH27) is characterized by small head circumference apparent in early childhood and associated with global developmental delay manifest as delayed walking, inability to walk, impaired intellectual development, and poor or absent speech. Most patients have variable and nonspecific additional features, including facial dysmorphism, hypotonia, limb hypertonia, poor feeding, and distal skeletal anomalies. Brain imaging may show enlarged ventricles or gyral abnormalities, but most have normal imaging (Parry et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).

CIMDAG syndrome (CIMDAG) is a multisystemic disorder characterized by severely impaired psychomotor development and hematologic abnormalities apparent from early infancy. Affected individuals show poor overall growth with microcephaly, impaired intellectual development, poor or absent speech, poor eye contact, and motor problems, such as inability to walk, hypotonia, and spasticity. Brain imaging typically shows cerebral and cerebellar atrophy, thin corpus callosum, and delayed myelination. The associated hematologic abnormalities are variable, but are mostly consistent with congenital dyserythropoietic anemia (CDA) (summary by Rodger et al., 2020 and Seu et al., 2020).

KINSSHIP syndrome (KINS) is an autosomal dominant disorder characterized by a recognizable pattern of anomalies including developmental delay, impaired intellectual development, seizures, mesomelic dysplasia, dysmorphic facial features, horseshoe or hypoplastic kidney, and failure to thrive (summary by Voisin et al., 2021).

Developmental and epileptic encephalopathy-96 (DEE96) is characterized by onset of seizures in the first days or weeks of life. Affected infants have tonic or myoclonic seizures associated with burst-suppression pattern on EEG. They also have hypotonia with respiratory insufficiency that may result in premature death. Those that survive have profound developmental delay and persistent seizures (summary by Suzuki et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Faundes-Banka syndrome (FABAS) is an autosomal dominant disorder characterized by variable combinations of developmental delay and microcephaly, as well as micrognathia and other dysmorphic features (Faundes et al., 2021).

Luo-Schoch-Yamamoto syndrome (LUSYAM) is a neurodevelopmental disorder characterized by global developmental delay and impaired intellectual development apparent from infancy. Affected individuals have delayed walking, early-onset seizures, hypotonia, dysmorphic facial features, and white matter abnormalities on brain imaging (Luo et al., 2021).

Galloway-Mowat syndrome-10 (GAMOS10) is a severe autosomal recessive disorder characterized by onset of symptoms soon after birth. Affected individuals have progressive renal dysfunction with proteinuria associated with diffuse mesangial sclerosis (DMS) on renal biopsy. Other features include global developmental delay, microcephaly, hypothyroidism, arachnodactyly, and dysmorphic facial features. Some patients may have seizures or abnormalities on brain imaging. All reported patients have died in infancy (summary by Arrondel et al., 2019 and Schmidt et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of GAMOS, see GAMOS1 (251300).

DYRK1A syndrome is characterized by intellectual disability including impaired speech development, autism spectrum disorder including anxious and/or stereotypic behavior problems, and microcephaly. Affected individuals often have a clinically recognizable phenotype including a typical facial gestalt, feeding problems, seizures, hypertonia, gait disturbances, and foot anomalies. The majority of affected individuals function in the moderate-to-severe range of intellectual disability; however, individuals with mild intellectual disability have also been reported. Other medical concerns relate to febrile seizures in infancy; the development of epilepsy with seizures of the atonic, absence, and generalized myoclonic types; short stature; and gastrointestinal problems. Ophthalmologic, urogenital, cardiac, and/or dental anomalies have been reported.

Childhood-onset neurodegeneration with progressive microcephaly (CONPM) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay apparent from infancy. The phenotype is highly variable: the most severely affected individuals have severe and progressive microcephaly, early-onset seizures, lack of visual tracking, and almost no developmental milestones, resulting in early death. Less severely affected individuals have a small head circumference and severely impaired intellectual development with poor speech and motor delay. Additional features may include poor overall growth, axial hypotonia, limb hypertonia with spasticity, undescended testes, and cerebral atrophy with neuronal loss (Lam et al., 2019 and Vanoevelen et al., 2022).

Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities (NEDSMBA) is an autosomal recessive disorder characterized by a core phenotype of moderate to profound developmental delay, progressive microcephaly, epilepsy, and periventricular calcifications (summary by Rosenhahn et al., 2022).

Autosomal recessive primary microcephaly-29 (MCPH29) is characterized by small head circumference apparent at birth and associated with global developmental delay, impaired intellectual development, speech delay, and behavioral abnormalities. Affected individuals also have poor overall growth with short stature, mild dysmorphic facial features, and seizures (Khan et al., 2020). For a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).

Developmental and epileptic encephalopathy-109 (DEE109) is characterized by the onset of various types of seizures in the first months or years of life. Affected individuals show developmental delay before and concurrent with the onset of seizures. Features include impaired intellectual development with poor speech, ataxic gait, coordination problems, and behavioral abnormalities (Manivannan et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Autosomal recessive primary microcephaly-30 (MCPH30) is characterized by small head circumference, poor overall growth, and global developmental delay with variably impaired intellectual development. Affected individuals have been reported to have variable additional congenital anomalies, including atrial septal defect, dysmorphic facial features, tracheal stenosis, and anomalies of the skin and teeth (Carvalhal et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).