Search

Anophthalmia and microphthalmia (A/M) are rare birth defects affecting up to 2 per 10,000 live births. These conditions are manifested by the absence of an eye or reduced eye volumes within the orbit leading to vision loss. Although clinical case series suggest a strong genetic component in A/M, few systematic investigations have been conducted on potential genetic contributions owing to low population prevalence. To overcome this challenge, we utilized DNA samples and data collected as part of the National Birth Defects Prevention Study (NBDPS). The NBDPS employed multi-center ascertainment of infants affected by A/M. We performed exome sequencing on 67 family trios and identified numerous genes affected by rare deleterious nonsense and missense variants in this cohort, including de novo variants. We identified 9 nonsense changes and 86 missense variants that are absent from the reference human population (Genome Aggregation Database), and we suggest that these are high priority candidate genes for A/M. We also performed literature curation, single cell transcriptome comparisons, and molecular pathway analysis on the candidate genes and performed protein structure modeling to determine the potential pathogenic variant consequences on PAX6 in this disease.

Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n = 26) are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441, a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T). All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to definitively support a causative role for variation in ZMYM3, the totality of the evidence, including 27 affected individuals, recurrent variation at two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally confirmed functional effects strongly support ZMYM3 as an NDD-associated gene.

Item does not contain fulltext Jansen-de Vries syndrome (JdVS) is a neurodevelopmental condition attributed to pathogenic variants in Exons 5 and 6 of PPM1D. As the full phenotypic spectrum and natural history remain to be defined, we describe a large cohort of children and adults with JdVS. This is a retrospective cohort study of 37 individuals from 34 families with disease-causing variants in PPM1D leading to JdVS. Clinical data were provided by treating physicians and/or families. Of the 37 individuals, 27 were male and 10 female, with median age 8.75 years (range 8 months to 62 years). Four families document autosomal dominant transmission, and 32/34 probands were diagnosed via exome sequencing. The facial gestalt, including a broad forehead and broad mouth with a thin and tented upper lip, was most recognizable between 18 and 48 months of age. Common manifestations included global developmental delay (35/36, 97%), hypotonia (25/34, 74%), short stature (14/33, 42%), constipation (22/31, 71%), and cyclic vomiting (6/35, 17%). Distinctive personality traits include a hypersocial affect (21/31, 68%) and moderate-to-severe anxiety (18/28, 64%). In conclusion, JdVS is a clinically recognizable neurodevelopmental syndrome with a characteristic personality and distinctive facial features. The association of pathogenic variants in PPM1D with cyclic vomiting bears not only medical attention but also further pathogenic and mechanistic evaluation. 01 juli 2023

Neurodevelopmental disorders (NDDs) often result from highly penetrant variation in one of many genes, including genes not yet characterized. Using the MatchMaker Exchange, we assembled a cohort of 22 individuals with rare, protein-altering variation in the X-linked transcriptional coregulator gene ZMYM3. Most (n=19) individuals were males; 15 males had maternally-inherited alleles, three of the variants in males arose de novo, and one had unknown inheritance. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n=21) are missense, two of which are recurrent. Three unrelated males were identified with inherited variation at R441, a site at which variation has been previously reported in NDD-affected males, and two individuals have de novo variation at R1294. All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is highly expressed in the brain, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one mutant, ZMYM3R1274W, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to support a conclusive causative role for variation in ZMYM3 in disease, the totality of the evidence, including the presence of recurrent variation, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally-confirmed functional effects, strongly supports ZMYM3 as a novel NDD gene.

SATB2-Associated syndrome (SAS) is an autosomal dominant, multisystemic, neurodevelopmental disorder due to alterations in SATB2 at 2q33.1. A limited number of individuals with 2q33.1 contiguous deletions encompassing SATB2 (ΔSAS) have been described in the literature. We describe 17 additional individuals with ΔSAS, review the phenotype of 33 previously published individuals with 2q33.1 deletions (n=50, mean age=8.5±7.8 years), and provide a comprehensive comparison to individuals with other molecular mechanisms that result in SAS (non-ΔSAS). Individuals in the ΔSAS group were often underweight for age (20/41=49%) with a progressive decline in weight (95% CI=-2.3 to -1.1, p

Several recurrent malformation associations affecting the development of the embryo have been described in which a genetic etiology has not been found, including LBWC, MURCS, OAVS, OEIS, POC, VACTERL, referred to here as "recurrent constellations of embryonic malformations" (RCEM). All are characterized by an excess of reported monozygotic discordant twins and lack of familial recurrence. We performed a comprehensive review of published twin data across all six phenotypes to allow a more robust assessment of the association with twinning and potential embryologic timing of a disruptive event. We recorded the type of twinning, any overlapping features of another RCEM, maternal characteristics, and the use of ART. Statistically significant associations included an excess of monozygotic twins and 80% discordance rate for the phenotype across all twins. There was an 18.5% rate of ART and no consistently reported maternal adverse events during pregnancy. We found 24 instances of co-occurrence of two RCEM, suggesting a shared pathogenesis across all RCEM phenotypes. We hypothesize the following timing for RCEM phenotypes from the earliest perturbation in development to the latest: LBWC, POC, OEIS, VACTERL, OAVS, then MURCS. The RCEM group of conditions should be considered a spectrum that could be studied as a group.

More than 50 individuals with activating variants in the receptor tyrosine kinase PDGFRB have been reported, separated based on clinical features into solitary myofibromas, infantile myofibromatosis, Penttinen syndrome with premature aging and osteopenia, Kosaki overgrowth syndrome, and fusiform aneurysms. Despite their descriptions as distinct clinical entities, review of previous reports demonstrates substantial phenotypic overlap. We present a case series of 12 patients with activating variants in PDGFRB and review of the literature. We describe five patients with PDGFRB activating variants whose clinical features overlap multiple diagnostic entities. Seven additional patients from a large family had variable expressivity and late-onset disease, including adult onset features and two individuals with sudden death. Three patients were treated with imatinib and had robust and rapid response, including the first two reported infants with multicentric myofibromas treated with imatinib monotherapy and one with a recurrent p.Val665Ala (Penttinen) variant. Along with previously reported individuals, our cohort suggests infants and young children had few abnormal features, while older individuals had multiple additional features, several of which appeared to worsen with advancing age. Our analysis supports a diagnostic entity of a spectrum disorders due to activating variants in PDGFRB. Differences in reported phenotypes can be dramatic and correlate with advancing age, genotype, and to mosaicism in some individuals.

ABHD16A (abhydrolase domain-containing protein 16A, phospholipase) encodes the major phosphatidylserine (PS) lipase in the brain. PS lipase synthesizes lysophosphatidylserine, an important signaling lipid that functions in the mammalian central nervous system. ABHD16A has not yet been associated with a human disease. In this report, we present a cohort of 11 affected individuals from six unrelated families with a complicated form of hereditary spastic paraplegia (HSP) who carry bi-allelic deleterious variants in ABHD16A. Affected individuals present with a similar phenotype consisting of global developmental delay/intellectual disability, progressive spasticity affecting the upper and lower limbs, and corpus callosum and white matter anomalies. Immunoblot analysis on extracts from fibroblasts from four affected individuals demonstrated little to no ABHD16A protein levels compared to controls. Our findings add ABHD16A to the growing list of lipid genes in which dysregulation can cause complicated forms of HSP and begin to describe the molecular etiology of this condition.

The increasing demand for advanced genomic services has finally come to the attention of healthcare systems and stakeholders who are now eager to find creative solutions to increase the pool of genomic literate providers. Training in genetics and dysmorphology has historically been conducted as a self-driven practice in pattern recognition, ideally within a formal or informal apprenticeship supervised by a master diagnostician. In recent times, case-based learning, framed by flipped classroom pedagogy have become the preferred teaching methods for complex medical topics such as genetics and genomics. To illuminate this perspective, our article was written in honor of the teaching style and pedagogy of Dr John M. Graham Jr and his lifelong commitment to medical education and mentoring.

Twins have an increased risk for congenital malformations and disruptions, including defects in brain morphogenesis. We analyzed data on brain imaging, zygosity, sex, and fetal demise in 56 proband twins and 7 less affected co-twins with abnormal brain imaging and compared them to population-based data and to a literature series. We separated our series into malformations of cortical development (MCD, N = 39), cerebellar malformations without MCD (N = 13), and brain disruptions (N = 11). The MCD group included 37/39 (95%) with polymicrogyria (PMG), 8/39 (21%) with pia-ependymal clefts (schizencephaly), and 15/39 (38%) with periventricular nodular heterotopia (PNH) including 2 with PNH but not PMG. Cerebellar malformations were found in 19 individuals including 13 with a cerebellar malformation only and another 6 with cerebellar malformation and MCD. The pattern varied from diffuse cerebellar hypoplasia to classic Dandy-Walker malformation. Brain disruptions were seen in 11 individuals with hydranencephaly, porencephaly, or white matter loss without cysts. Our series included an expected statistically significant excess of monozygotic (MZ) twin pairs (22/41 MZ, 54%) compared to population data (482/1448 MZ, 33.3%; p = .0110), and an unexpected statistically significant excess of dizygotic (DZ) twins (19/41, 46%) compared to the literature cohort (1/46 DZ, 2%; p < .0001. Recurrent association with twin-twin transfusion syndrome, intrauterine growth retardation, and other prenatal factors support disruption of vascular perfusion as the most likely unifying cause.

Cerebellar malformations are diverse congenital anomalies frequently associated with developmental disability. Although genetic and prenatal non-genetic causes have been described, no systematic analysis has been performed. Here, we present a large-exome sequencing study of Dandy-Walker malformation (DWM) and cerebellar hypoplasia (CBLH). We performed exome sequencing in 282 individuals from 100 families with DWM or CBLH, and we established a molecular diagnosis in 36 of 100 families, with a significantly higher yield for CBLH (51%) than for DWM (16%). The 41 variants impact 27 neurodevelopmental-disorder-associated genes, thus demonstrating that CBLH and DWM are often features of monogenic neurodevelopmental disorders. Though only seven monogenic causes (19%) were identified in more than one individual, neuroimaging review of 131 additional individuals confirmed cerebellar abnormalities in 23 of 27 genetic disorders (85%). Prenatal risk factors were frequently found among individuals without a genetic diagnosis (30 of 64 individuals [47%]). Single-cell RNA sequencing of prenatal human cerebellar tissue revealed gene enrichment in neuronal and vascular cell types; this suggests that defective vasculogenesis may disrupt cerebellar development. Further, de novo gain-of-function variants in PDGFRB, a tyrosine kinase receptor essential for vascular progenitor signaling, were associated with CBLH, and this discovery links genetic and non-genetic etiologies. Our results suggest that genetic defects impact specific cerebellar cell types and implicate abnormal vascular development as a mechanism for cerebellar malformations. We also confirmed a major contribution for non-genetic prenatal factors in individuals with cerebellar abnormalities, substantially influencing diagnostic evaluation and counseling regarding recurrence risk and prognosis.

The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as “GENE-related phenotype descriptor” (e.g., “CFTR-related cystic fibrosis”). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.

Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a "Dubowitz-like" condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome-wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy-number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next-generation sequencing. Overall, the DubS-like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.

The identification of genetic variants implicated in human developmental disorders has been revolutionized by second-generation sequencing combined with international pooling of cases. Here, we describe seven individuals who have diverse yet overlapping developmental anomalies, and who all have de novo missense FBXW11 variants identified by whole exome or whole genome sequencing and not reported in the gnomAD database. Their phenotypes include striking neurodevelopmental, digital, jaw, and eye anomalies, and in one individual, features resembling Noonan syndrome, a condition caused by dysregulated RAS signaling. FBXW11 encodes an F-box protein, part of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex, involved in ubiquitination and proteasomal degradation and thus fundamental to many protein regulatory processes. FBXW11 targets include β-catenin and GLI transcription factors, key mediators of Wnt and Hh signaling, respectively, critical to digital, neurological, and eye development. Structural analyses indicate affected residues cluster at the surface of the loops of the substrate-binding domain of FBXW11, and the variants are predicted to destabilize the protein and/or its interactions. In situ hybridization studies on human and zebrafish embryonic tissues demonstrate FBXW11 is expressed in the developing eye, brain, mandibular processes, and limb buds or pectoral fins. Knockdown of the zebrafish FBXW11 orthologs fbxw11a and fbxw11b resulted in embryos with smaller, misshapen, and underdeveloped eyes and abnormal jaw and pectoral fin development. Our findings support the role of FBXW11 in multiple developmental processes, including those involving the brain, eye, digits, and jaw.

This chapter reviews background information about the incidence, risk factors, genetics, family history, recurrence risk, and epidemiology of isolated and syndromic neural tube defects. The various subtypes of NTD are described including common, lethal and rare presentations such as sacral agenesis and anterior meningomyelocele. Prenatal therapy with in utero surgery is addressed. The discussion on the differential diagnosis of neural tube defects summarizes its common causes, including teratogenic agents, chromosome anomalies (trisomy 18), and Mendelian disorders that cause isolated NTDs and syndromic NTDs that are associated with malformations in other organ systems. The chapter gives recommendations for evaluation and management. A clinical case presentation features an infant with a lumbosacral meningomyelocele caused by valproic acid embryopathy.

This chapter reviews background information about the incidence, risk factors, family history, genetics, recurrence risk, and epidemiology of isolated and syndromic hypospadias and some disorders of sex development (DSD)—6,XY DSD and 46,XX DSD. The associations with male factor infertility, intracytoplasmic sperm injection, low birth weight, and low anoscrotal distance are discussed. The differential diagnosis of genital anomalies summarizes common causes, including teratogenic agents, chromosome anomalies, including copy number variants, Mendelian disorders that also affect musculoskeletal, skeletal, and connective tissues, and it gives recommendations for evaluation and management. A clinical case presentation features an infant conceived by in vitro fertilization with severe early IUGR and hypospadias.

This chapter reviews background information about the incidence, risk factors, sex ratio, genetics, family history, recurrence risk, and epidemiology of the various types of isolated and syndromic Hirschsprung disease. Distinctions that characterize long segment, short segment, zonal, total colonic, and total intestinal aganglionosis are reviewed. The discussion on the differential diagnosis of Hirschsprung disease summarizes its common causes, including chromosome anomalies (Down syndrome and recurrent microdeletions), and Mendelian traits associated with isolated disease and syndromic aganglionosis with non-GI malformations. This chapter includes gives recommendations for evaluation and management. A clinical case presentation features an SGA microcephalic infant who failed to pass meconium with Goldberg–Shprintzen syndrome.

This book was written to assist clinicians who care for newborns with congenital abnormalities in their diagnosis, genomic testing, and management. The goal was to make the evaluation of common neonatal anomalies and genetic syndromes accessible and understandable. In addition, the book may serve as an initial guide for practitioners in areas in which clinical genetic expertise is not readily available. As the book was being written, the testing paradigm shifted to a genomic approach: Chromosome analysis gave way to microarrays, and single gene testing was largely replaced by gene panels and exome sequencing. Thus, this book, which was initially intended as a clinical primer, of necessity became a resource for gene-based information as well.

This chapter reviews the incidence, risk factors, and epidemiology of disorders associated with twinning. The timing of twinning and the types of twins are reviewed. The fetal and perinatal complications of twinning including twin to twin transfusion and its treatment are discussed, as well as the possible consequences of death of a monozygotic co-twin. These include severe disruptive brain abnormalities, and other vascular disruptive defects. The birth defects more common in twins are enumerated and specific patterns of birth defects such as hemifacial macrosomia and VACTERL are discussed. A clinical case presentation features monozygotic twins with twin-to-twin transfusion syndrome and congenital heart disease.

This chapter reviews the incidence, risk factors, genetics, recurrence risk, and epidemiology of isolated and syndromic non-immune hydrops fetalis (NIH). The discussion on the differential diagnosis of various types of NIH summarizes common causes, including chromosome anomalies (Down syndrome, Turner syndrome and others), congenital infections ( CMV, Parvovirus and Syphilis) , and multiple congenital anomaly syndromes (Noonan spectrum disorders, Neu Laxova syndrome, Hennekam syndrome and others), skeletal dysplasias and a number of lysosomal storage diseases. A through evaluation both before and after birth including maternal history, infectious work-up, microarray, autopsy and selected molecular testing including exome sequencing can achieve a diagnosis in an increasing number of cases. The mortality and morbidity of NIH remains high and relatively few are amenable to specific interventions. A clinical case presentation features an infant with congenital parvovirus B19 infection.

This chapter reviews background information about the incidence, risk factors, genetics, family history, recurrence risk, and epidemiology of isolated and syndromic congenital cardiac anomalies, including septal defects, patent ductus, conotruncal defects, left ventricular outflow tracto obstruction, and congenital intracardiac tumors. The discussion on the differential diagnosis of various types of cardiac anomalies summarizes common causes, including teratogenic agents (pregestational diabetes, maternal phenylketonuria), chromosome anomalies (aneuploidy, recurrent microdeletions, and other copy number variants), and Mendelian disorders associated with multiple congenital anomalies. The chapter gives recommendations for evaluation and management. A clinical case presentation features an infant with a rhabdomyoma caused by tuberous sclerosis.

This chapter reviews the incidence, epidemiology, genetics, and anatomical varieties of congenital anomalies of the lower extremity. Defects can be transverse, longitudinal, intercalary, or central and involve the femur, tibia, or fibula and there are combined defects and conditions affecting both upper and lower extremity. Isolated transverse defects are less common in the lower extremity than the upper but amniotic band disruption sequence can affect both upper and lower limbs. Adams Oliver syndrome affects both upper and lower limbs. Femoral facial syndrome is the most common lower extremity syndrome. Split hand/split foot is clinically heterogeneous and complex albeit with several well characterized syndromes including those caused by variants in TP63 and the 17p1.3. chromosome duplicaton syndrome . The clinical case presentation features an infant with fibular aplasia, tibial campomelia, and oligosyndactyly due to FATCO syndrome, a condition whose genetic cause is unknown.

This chapter reviews background information about the incidence, risk factors, genetics, recurrence risk, and epidemiology of congenital anomalies of the renal and urinary tract (CAKUT) including hydronephrosis, horseshoe kidney, renal agenesis, multicystic dysplastic kidneys, and polycystic kidneys, congenital nephrotic syndromes, bladder and cloacal exstrophy, and obstructive uropathies. The discussion on the differential diagnosis of CAKUT summarizes common causes of various structural and functional renal anomalies and obstructive uropathies, including teratogenic agents, chromosome anomalies, monogenetic renal anomalies, and multiple malformation syndromes. Mendelian renal disorders that feature associated nonrenal anomalies such as craniofacial disorders, eye anomalies, skeletal dysplasias, CNS anomalies, and ciliopathies are reviewed. The chapter gives recommendations for evaluation and management. A clinical case presentation features an infant with renal tubular dysgenesis.

This chapter reviews the incidence, risk factors, genetics, recurrence risk, and epidemiology of perinatal arterial stroke (PAS). This type of stroke is distinct from later stroke in the pediatric age group. This disorder is the most common cause of hemiplegic cerebral palsy and the frequency has remained stable despite advances in fetal monitoring and liberal use of cCesarean section. Fetal and maternal risk factors include post-dates, large and small fetal size, chorioamnionitis, and a prolonged second stage of labor. Neonatal seizures are the most common presenting sign in term newborns. The role of thrombophilic factors in causation is controversial. COL4A1 and COL4A2 variants may mimic PAS and testing for this cause should be considered. Follow up of PAS needs to be long term as neurologic and ophthalmologic sequelae can be delayed. The clinical case features a large for gestational age, macrocephalic infant with a perinatal arterial stroke.

This chapter reviews the congenital blistering syndromes. These include the many forms of epidermolysis bullosa (EB) of which the simplex form is the most common. Junctional and dystrophic EB and Kindler syndrome are the other major types of EB. The differential also includes Peeling Skin syndrome and other common forms of neonatal blisters due to infection, maternal disease or other genetic disorders. Genetic sequencing panels are rapidly replacing dermatopathology in the diagnosis of these complex and overlapping conditions. Multidisciplinary care is necessary for severely affected infants and some disorders are lethal in the neonatal period. The clinical case presentation features an infant with autosomal recessive lethal acantholytic epidermolysis bullosa.

This chapter reviews the incidence, genetics, and classification of osteogenesis imperfecta (OI) and other bone fragility syndromes that can present with fractures in the newborn. A few rare recessive disorders including Stuve Wiedemann syndrome are discussed briefly. Distinquishing clinical features are highlighted. The utility of gene panels in the differential diagnosis of these disorders is presented. Therapeutic advances including the use of bisphosphonates and asfotase alfa in disorders with increased fracture risk can be expected to increase. Non-accidental injury, is discussed briefly as is the differential diagnosis of rickets, including that associated with prematurity. The clinical case presentation features an infant with osteogenesis imperfecta type IV.

This chapter reviews background information about the incidence, risk factors, genetics, recurrence risk, and epidemiology of single suture and multiple suture craniosynostosis including isolated and syndromic varieties. The discussion on the differential diagnosis of craniosynostosis summarizes its common causes, including teratogenic agents (fluconazole, maternal thyroid disorders, methotrexate, valproic acid), chromosome anomalies, and Mendelian disorders that involve extracranial malformations. The relationship between premature closure of cranial sutures of postnatal onset and positional plagiocephaly, prematurity, and microcephaly are examined. This chapter provides recommendations for testing, evaluation and management. A clinical case presentation features an infant with Saethre–Chotzen syndrome, whose mildly affected relatives had not been diagnosed.

This chapter reviews the incidence, genetics, recurrence risk, and the more common life-limiting skeletal dysplasias. The discussion on the differential diagnosis of these severe skeletal dysplasias summarizes their distinctive clinical and radiographic features and prognosis. The most common of these is Thanatophoric dysplasia. Other reviewed disorders include Campomelic dysplasia, Achondrogenesis, the Short Rib Polydactyly syndromes, Atelosteogenesis, rhizomelic chondrodysplasia punctata, and perinatal hypophoshatasia. The potential to alter the lethal natural history of formerly lethal hypophosphatasia by immediate treatment with asofostase alfa is highlighted. Recommendations for genetic panel testing, other evaluations, and parental counseling are provided. The clinical case presentation features an infant with Thanatophoric dysplasia.

This chapter reviews background information about the incidence and epidemiology of common teratogenic agents, including prescription medications and congenital infections such as LCMV, parvovirus, TORCH, syphilis, and Zika. The characteristic fetal effects of in utero exposure to ACE inhibitors, anticoagulants, anticonvulsants, folic acid antagonists, immunosuppresants, and Vitamin A derivatives are reviewed. The teratogenic effects associated with chronic maternal disorders, such as gastric bypass surgery, hyperemesis gravidarum, hypertension, hyperthyroidism, and maternal phenylketonuria are discussed. The differential diagnosis includes Mendelian disorders with similar phenotypes. The chapter includes recommendations for evaluation and management. A clinical case presentation features an infant with first-trimester exposure to misoprostol (Cytotec).

This chapter reviews the incidence, risk factors, genetics, recurrence risk, epidemiology, and distinctive anatomy of gastroschisis. This abnormality is much more common in the offspring of young mothers and the overall incidence continues to rise worldwide. Other risk factors include short intrapregnancy intervals, smoking and several medications such as aspirin and ibuprophen. Associated abnormalities most frequently include intestinal atresias and strictures although other vascular disruptive defects, particularly the amyoplasia form of arthrogryposis, are seen in 3-10%. Distinquishing this defect from omphalocele is usually not difficult although a ruptured omphalocele may cause confusion. Ruling out limb-body wall disruption is important as the prognosis is vastly different. The clinical case presentation features an infant with amyoplasia and gastroschisis.

This chapter reviews the incidence, risk factors, genetics, recurrence risk, and epidemiology of isolated and syndromic microcephaly. The differential diagnosis of microcephaly includes multiple teratogenic agents such as alcohol, hyperthermia, maternal PKU, and new and old congenital infections as well as specific chromosome aneuploidies such as 4p- and 5p- where microcephaly is almost universally seen. Metabolic disorders include congenital disorders of glycosylation and pyruvate dehydrogenase deficiency. Multiple autosomal recessive primary microcephaly syndromes (MCPH) are being delineated. Important syndromes with microcephaly include Cornelia de Lange and Smith Lemli Opitz syndromes but many other complex genetic syndromes include microcephaly. A clinical case presentation features an infant with autosomal recessive primary microcephaly with an unknown genetic cause.

This chapter reviews miscellaneous congenital skin disorders, including albinism, pigmentary dysplasias, and cutis aplasia. Oculocutaneous albinism I is the form of albinism most likely to be diagnosed in the neonate. Other forms present later in infancy or childhood. Prader-Willi syndrome and Angelman syndrome children are frequently hypopigmented due to involvement of the OCA2 locus. Localized hypopigmentation is seen in several forms of Waardenburg syndrome. Cutis aplasia can have a myriad of causes, some benign and others associated with serious chromosomal disorders or syndromes. Pigmentary mosaicism for chromosomal abnormalities or single gene variantschanges cause streaky pigmentarytion changes previously termed hypomelanosis of Ito. Microarray, gene sequencing panels or single gene testing in a tissue other than blood may establish the diagnosis in those syndromes that are mosaic. A clinical case presentation features an infant with oculocutaneous albinism type I.

This chapter reviews isolated and syndromic causes of macrocephaly and megalencephaly. The two terms are usually but not always interchangeable. The differential diagnosis of macrocephaly includes familial macrocephaly, chromosome duplications and deletions, metabolic disorders and complex somatic mosaic conditions including CLOVES, MCAP and MPPH. Single gene disorders with macrocephaly include those in the Noonan syndrome spectrum (RASopathies). Syndromes with hemimegalencephaly, including linear nevus sebaceous and tuberous sclerosis are briefly reviewed. Many syndromes with macrocephaly have associated overgrowth and are covered in the Overgrowth chapter as well, including Weaver, Sotos and Malan syndromes. A clinical case presentation features an infant with basal cell nevus syndrome.

This chapter reviews background information about the incidence, epidemiology, genetics, and other anomalies associated with common congenital anomalies of the upper extremity. The discussion reviews the differential diagnosis of transverse, longitudinal (amelia, radial, ulnar), intercalary (phocomelia), and central (split hand/foot) defects of the radius and ulna and combined upper and lower extremity defects. The chapter summarizes common causes of upper extremity anomalies, including amniotic band disruption sequence, teratogenic agents (misoprostol, thalidomide, valproic acid), vascular disruption, chromosome anomalies, and Mendelian congenital malformation syndromes, and it gives recommendations for evaluation and management. A clinical case presentation features an infant with Holt–Oram syndrome.

This chapter reviews information on disorders that cause large birth weight, macrosomia, and/or segmental overgrowth. The most common of these conditions is seen in infants of diabetic mothers. Abnormal dosage of growth regulating genes make chromosomal microarray abnormalities a relatively common cause of overgrowth. Particularly notable is the distinctive Pallister Killian syndrome (12p tetrasomy). Other common overgrowth syndromes include Beckwith-Wiedemann syndrome, Sotos, Malan, and Weaver syndromes. The RASopathy syndromes including Noonan syndrome* and Costello syndrome are also often large at birth. Segmental overgrowth syndromes including Proteus and Klippel Trenaunay as well as PIK3CA related overgrowth (PROS) are discussed as well as their somatic mosaic origin in affected tissues. Clinical guidelines for evaluation and surveillance are outlined. The clinical case presentation features an infant with Sotos syndrome.

This chapter reviews background information about the incidence, risk factors, family history, genetics, recurrence risk, and epidemiology of isolated and syndromic cleft lip with or without cleft palate. Microforms of cleft lip are described. The distinctive anatomy of bilateral cleft lip is contrasted with premaxillary agenesis, a wider defect caused by absence of the frontonasal process. The discussion on the differential diagnosis of cleft lip summarizes its common causes, including teratogenic agents (alcohol, maternal diabetes, phenytoin), chromosome anomalies (aneuploidy, recurrent deletion syndromes), and Mendelian clefting disorders that include associated malformations in other organ systems. The chapter gives recommendations for evaluation and management. A clinical case presentation features an infant with an oral cleft who has a positive family history of cleft lip and palate with paramedian lip pits due to Van der Woude syndrome.

This chapter reviews background information about the incidence, risk factors, genetics, recurrence risk, family history and epidemiology of isolated and syndromic ear anomalies. The discussion on the differential diagnosis of ear anomalies summarizes its common causes, including teratogenic agents (isotretinoin, maternal diabetes, mycophenylate), chromosome anomalies (aneuploidy, 22q11 deletion), common sporadic multiple congenital anomaly syndromes (Hemifacial microsomia/Goldenhar), and Mendelian disorders that are primarily craniofacial (Treacher-Collins and other mandibulofacial dysostoses) and others that include malformations in other organ systems (CHARGE). The chapter gives recommendations for evaluation and management. A clinical case presentation features a child with mycophenylate embryopathy, who had been incorrectly diagnosed with Treacher Collins syndrome.

This chapter reviews background information about the incidence, risk factors, genetics, recurrence risk, and epidemiology of isolated and syndromic cerebellar hypoplasia, agenesis and dysgenesis, cerebellar vermis hypoplasia, Dandy Walker malformation and other cerebellar anomalies. The relationship between isolated unilateral cerebellar lesions and in utero infarction or vascular disruption is described. The discussion on the differential diagnosis of cerebellar anomalies summarizes common causes, including teratogenic agents (CMV, Herpes), chromosome anomalies (aneuploidy, copy number variants), metabolic disorders and Mendelian traits associated with malformations in other parts of the CNS and in other organ systems, including the ciliopathies. The chapter offers recommendations for evaluation and management. A clinical case presentation features an infant with rhombocephaosynapsis, aqueductal stenosis, and biparietal alopecia caused by Gomez–Lopez–Hernandez syndrome.

This chapter reviews background information about the prevalence, sex ratio, genetics, recurrence risk and epidemiology of isolated and syndromic preaxial, postaxial and mesoaxial (central) polydactyly of the hands and feet. Various patterns of isolated and bilateral polydactyly and common associated malfomations (syndactyly, craniosynsostosis, GI anomalies, macrocephaly, mocrpcephaly, renal cysts) are described. The discussion on the differential diagnosis of polydactyly summarizes its common causes, including teratogenic agents, diabetic embryopathy, chromosome anomalies, and congenital malformation syndromes caused by Mendelian traits. It gives recommendations for evaluation and management. A clinical case presentation features an infant with tibial hypoplasia/aplasia with polydactyly (Werner mesomelic syndrome).

This chapter reviews the incidence, risk factors, genetics, recurrence risk, and epidemiology of arthrogryposis. The most common and clinically recognizable type among the congenital contractures is amyoplasia, and treatment options are improving the quality of life for these patients. The distal arthrogryposes are mostly autosomal dominant and caused by an increasing number of genes including variants in PIEZ02 and MYH3 among several others. The lethal contracture syndromes have an expanding number of causes many of which are autosomal recessive. The majority of these conditions are recognized on US. In viable syndromes the early and intensive use of physical therapy is critical and can result in significant joint mobilization. The clinical case presentation features an infant with lethal multiple pterygia syndrome.

The Na+/K+- ATPase acts as an ion pump maintaining the essential plasma membrane potential in all mammalian cell types, and is essential for many cellular functions. There are four α isoforms (α1, α2, α3 and α4) with distinct expression patterns, kinetic properties and substrate affinity. The α2-isoform is encoded by ATP1A2 and evidence supports its utmost importance in Cl- homeostasis in neurons, and in the function of respiratory neurons at birth. Monallelic pathogenic variants in ATP1A2 are associated with familial hemiplegic migraine type 2 (FHM2) and on rare occasions with alternating hemiplegia of childhood 1 (AHC1). To date, no instances of biallelic loss of function variants have been reported in humans. However, Atp1a2 homozygous loss of function knockout mice (α2-/- mice) show severe motor deficits, with lack of spontaneous movements, and are perinatally lethal due to absent respiratory activity. In this report we describe three newborns from two unrelated families, who died neonatally, presenting in utero with an unusual form of fetal hydrops, seizures and polyhydramnios. At birth they had multiple joint contractures (e.g. arthrogryposis), microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic loss of function variants in ATP1A2, predicted to be pathogenic were found on whole exome sequencing. We propose that this is a distinctive new syndrome caused by complete absence of Na+/K+- ATPase α2-isoform expression.

The human general transcription factor TFIID is composed of the TATA-binding protein (TBP) and 13 TBP-associated factors (TAFs). In eukaryotic cells, TFIID is thought to nucleate RNA polymerase II (Pol II) preinitiation complex formation on all protein coding gene promoters and thus, be crucial for Pol II transcription. In a child with intellectual disability, mild microcephaly, corpus callosum agenesis and poor growth, we identified a homozygous splice-site mutation in TAF8 (NM_138572.2: c.781-1G > A). Our data indicate that the patient's mutation generates a frame shift and an unstable TAF8 mutant protein with an unrelated C-terminus. The mutant TAF8 protein could not be detected in extracts from the patient's fibroblasts, indicating a loss of TAF8 function and that the mutation is most likely causative. Moreover, our immunoprecipitation and proteomic analyses show that in patient cells only partial TAF complexes exist and that the formation of the canonical TFIID is impaired. In contrast, loss of TAF8 in mouse embryonic stem cells and blastocysts leads to cell death and to a global decrease in Pol II transcription. Astonishingly however, in human TAF8 patient cells, we could not detect any cellular phenotype, significant changes in genome-wide Pol II occupancy and pre-mRNA transcription. Thus, the disorganization of the essential holo-TFIID complex did not affect global Pol II transcription in the patient's fibroblasts. Our observations further suggest that partial TAF complexes, and/or an altered TFIID containing a mutated TAF8, could support human development and thus, the absence of holo-TFIID is less deleterious for transcription than originally predicted.

Summary De novo germline mutations in the RNA helicase DDX3X account for 1%–3% of unexplained intellectual disability (ID) cases in females and are associated with autism, brain malformations, and epilepsy. Yet, the developmental and molecular mechanisms by which DDX3X mutations impair brain function are unknown. Here, we use human and mouse genetics and cell biological and biochemical approaches to elucidate mechanisms by which pathogenic DDX3X variants disrupt brain development. We report the largest clinical cohort to date with DDX3X mutations (n = 107), demonstrating a striking correlation between recurrent dominant missense mutations, polymicrogyria, and the most severe clinical outcomes. We show that Ddx3x controls cortical development by regulating neuron generation. Severe DDX3X missense mutations profoundly disrupt RNA helicase activity, induce ectopic RNA-protein granules in neural progenitors and neurons, and impair translation. Together, these results uncover key mechanisms underlying DDX3X syndrome and highlight aberrant RNA metabolism in the pathogenesis of neurodevelopmental disease.

SHORT syndrome has historically been defined by its acronym: short stature (S), hyperextensibility of joints and/or inguinal hernia (H), ocular depression (O), Rieger abnormality (R) and teething delay (T). More recently several research groups have identified PIK3R1 mutations as responsible for SHORT syndrome. Knowledge of the molecular etiology of SHORT syndrome has permitted a reassessment of the clinical phenotype. The detailed phenotypes of 32 individuals with SHORT syndrome and PIK3R1 mutation, including eight newly ascertained individuals, were studied to fully define the syndrome and the indications for PIK3R1 testing. The major features described in the SHORT acronym were not universally seen and only half (52%) had four or more of the classic features. The commonly observed clinical features of SHORT syndrome seen in the cohort included intrauterine growth restriction (IUGR)