The Foundation Fighting Blindness is a 50‐year old 501c(3) non‐profit organization dedicated to supporting the development of treatments and cures for people affected by the inherited retinal diseases (IRD), a group of clinical diagnoses that include orphan diseases such as retinitis pigmentosa, Usher syndrome, and Stargardt disease, among others. Over $760 M has been raised and invested in preclinical

Genetic eye diseases are phenotypically and genetically heterogeneous, affecting 1 in 1,000 people worldwide. This prevalence can increase in populations where endogamy is a social preference, such as in Arab populations. A retrospective consecutive cohort of 91 patients from 74 unrelated families affected with non‐syndromic and syndromic inherited eye disease presenting to the ocular genetics service

Pathogenic variants in the gene HGSNAT (heparan‐α ‐glucosaminide N ‐acetyltransferase) have been reported to underlie two distinct recessive conditions, depending on the specific genotype, mucopolysaccharidosis type IIIC (MPSIIIC)—a severe childhood‐onset lysosomal storage disorder, and adult‐onset nonsyndromic retinitis pigmentosa (RP). Here we describe the largest cohort to‐date of HGSNAT ‐associated

Sex chromosome abnormalities (SCAs) are characterized by gain or loss of entire sex chromosomes or parts of sex chromosomes with the best‐known syndromes being Turner syndrome, Klinefelter syndrome, 47,XXX syndrome, and 47,XYY syndrome. Since these syndromes were first described more than 60 years ago, several papers have reported on diseases and health related problems, neurocognitive deficits, and

Since the first description of Klinefelter syndrome (KS) was published in 1942 in The Journal of Clinical Endocrinology , large inter‐individual variability in the phenotypic presentation has been demonstrated. However, our understanding of the global impact of the additional X chromosome on the genome remains an enigma. Evidence from the existing literature of KS indicates that not just one single

One of the two X chromosomes in females is epigenetically inactivated, thereby compensating for the dosage difference in X‐linked genes between XX females and XY males. Not all X‐linked genes are completely inactivated, however, with 12% of genes escaping X chromosome inactivation and another 15% of genes varying in their X chromosome inactivation status across individuals, tissues or cells. Expression

Klinefelter syndrome (KS; 47,XXY) is the most common sex chromosomal anomaly and causes a multitude of symptoms. Often the most noticeable symptom is infertility caused by azoospermia with testicular histology showing hyalinization of tubules, germ cells loss, and Leydig cell hyperplasia. The germ cell loss begins early in life leading to partial hyalinization of the testis at puberty, but the mechanistic

Sex chromosome trisomies (SCTs) (XXX, XXY, and XYY karyotypes) are associated with an elevated risk of neurodevelopmental disorders. The range of severity of the phenotype is substantial. We considered whether this variable outcome was related to the presence of copy number variants (CNVs)—stretches of duplicated or deleted DNA. A sample of 125 children with an SCT were compared with 181 children of

Klinefelter syndrome (KS, 47,XXY) is the most frequent male chromosomal aneuploidy resulting in a highly heterogeneous clinical phenotype associated with hormonal dysbalance, increased rate of co‐morbidities, and reduced lifespan. Two hallmarks of KS‐affecting testicular functions are consistently observed: Hypergonadotropic hypogonadism and germ cell (GC) loss resulting in infertility. Although KS

47,XXX (triple X) and Turner syndrome (45,X) are sex chromosomal abnormalities with detrimental effects on health with increased mortality and morbidity. In karyotypical normal females, X‐chromosome inactivation balances gene expression between sexes and upregulation of the X chromosome in both sexes maintain stoichiometry with the autosomes. In 47,XXX and Turner syndrome a gene dosage imbalance may

More and more women rely on non‐invasive prenatal screening (NIPS) to detect fetal sex and risk for aneuploidy. The testing applies massively parallel sequencing or single nucleotide polymorphism (SNP) microarray to circulating cell‐free DNA to determine relative copy number. In addition to trisomies 13, 18, and 21, some labs offer screening for sex chromosome abnormalities as part of their test. In

Klinefelter syndrome (KS) is the most frequent sex chromosomal aneuploidy. The karyotype 47,XXY originates from either paternal or maternal meiotic nondisjunction during gametogenesis. KS males are very likely to exhibit marked gonadal dysfunctions, presenting both in severely attenuated spermatogenesis as well as hypergonadotropic hypogonadism. In addition, neurocognitive and psychosocial impairments

Klinefelter syndrome is highly underdiagnosed and diagnosis is often delayed. With the introduction of non‐invasive prenatal screening, the diagnostic pattern will require an updated description of the clinical and biochemical presentation of infants with Klinefelter syndrome. In the first months of life, the hypothalamic–pituitary–gonadal (HPG)‐axis is transiently activated in healthy males during

Klinefelter syndrome (KS) occurs in 1:600 males and is associated with high morbidity and mortality due to diabetes and cardiovascular disease. Up to 50% of men with KS have metabolic syndrome, a cluster of features conferring increased risk for diabetes and cardiovascular disease. These cardiometabolic (CM) risk features have not been studied in adolescents with KS. The objective of this cohort study

Klinefelter syndrome (KS), which normally presents with a 47,XXY karyotype, is the most common sex chromosome disorder in males. It is also the most common genetic cause of male infertility. KS subjects are typically tall, with small and firm testes, gynecomastia, broad hips, and sparse body hair, although a less evident presentation is also possible. KS is also characterized by a high prevalence of

Klinefelter syndrome (KS; 47,XXY) is the most common sex chromosome abnormality in males (150 per 100,000 males). The condition leads to hypergonadotropic hypogonadism and ever since the condition was described approximately 80 years ago, testosterone treatment has been the cornerstone in care for individuals with KS. However, KS is associated with an array of health‐related and socioeconomic challenges

Klinefelter syndrome (KS) is a quite common disorder with an incidence of 1–2 in 1,000 new‐born males. Most patients are diagnosed in the light of a clinical checkup when consulting a fertility clinic with an unfulfilled child wish. Infertility in KS patients is caused by a massive germ cell loss, leading to azoospermia in more than 90% of the adult patients. Most seminiferous tubules in the adult

An additional Y chromosome occurs in ~1 in 1,000 males, resulting in the karyotype 47,XYY. The phenotype includes tall stature, hypotonia, neuropsychiatric comorbidities, and an increased risk of infertility in adulthood. Little is known about testicular function in childhood and adolescence in 47,XYY. This cross‐sectional study aimed to assess testicular function serum biomarkers, including total

While the most common Sex Chromosome Aneuploidy (SCA) is 47,XXY, other variations, such as 48,XXYY, are less studied, perhaps due to its rarity. 48,XXYY occurs with an estimated prevalence of 1:18,000–40,000 male births. This SCA is associated with a variety of complex physical, psychological, and neuroanatomical findings. The purpose of this integrative review is to summarize the available evidence

Sex chromosome aneuploidies (SCAs) are the most commonly occurring aneuploidies in children with a collective prevalence rate of 1 in 500 live births. Prior research has documented SCAs are associated with an increased risk for early expressive language and gross motor delays, learning disorders, ADHD, autism spectrum disorder, anxiety, and executive function problems. Although SCAs have been historically

Sex chromosome trisomies (SCT), including Klinefelter syndrome/XXY, Trisomy X, and XYY syndrome, occur in 1 of every 500 births. The past decades of research have resulted in a broadening of known associated medical comorbidities as well as advances in psychological research. This review summarizes what is known about early neurodevelopmental, behavioral, and medical manifestations in young children

Children with SCT have an increased risk of suboptimal neurodevelopment. Previous studies have shown an elevated risk for neurobehavioral problems in individuals with SCT. However, not much is known about neurobehavioral problems in very young children; knowledge that could help with early identification of children at risk for suboptimal development, and that could help establish targets for early

Identifying the factors related to adaptive functioning will improve the information available to families and providers of females with Trisomy X. Cognitive and behavioral features were assessed in 50 females ages 12.2 ± 3.6 years using the Behavior Assessment System for Children Second Edition (BASC‐2) and Wechsler Scales of Intelligence. Executive functioning, social skills, and autistic traits

Few studies have systematically assessed executive functioning (EF) skills in boys with XXY, and these are limited by small samples and restricted EF assessment. This study used a broader battery of performance‐based measures as well as parent‐rating scales of EF in 77 boys and adolescents with XXY (mean age = 12.5 years), recruited from a clinical trial and an outpatient clinic. Exploratory factor

A few studies have examined neuropsychological functions, sleep, and mental health combined in Klinefelter syndrome (KS; 47,XXY). We investigated neuropsychological functions with standard tests, sleep with actigraphy, and self‐reported mental health in 30 men with KS (Mean age = 36.7 years) compared to 21 controls (Mean age = 36.8 years). Men with KS scored significantly lower on mental speed, attention

Sex chromosome aneuploidy (SCA) increases the risk for cognitive deficits, and confers changes in regional cortical thickness (CT) and surface area (SA). Neuroanatomical correlates of inter‐individual variation in cognitive ability have been described in health, but are not well‐characterized in SCA. Here, we modeled relationships between general cognitive ability (estimated using full‐scale IQ [FSIQ]

Klinefelter syndrome (KS; 47,XXY) impacts neurodevelopment and is associated with an increased risk of cognitive, psychological and social impairments, although significant heterogeneity in the neurodevelopmental profile is seen. KS is characterized by a specific cognitive profile with predominantly verbal deficits, preserved function in non‐verbal and visuo‐spatial domains, executive dysfunction and

Sex chromosome aneuploidies (SCA) are associated with an increased risk for specific learning disorders (SLD). Individuals with Klinefelter Syndrome (KS) show an increased incidence of developmental dyslexia and individuals with Turner Syndrome (TS) are often affected by developmental dyscalculia. Accordingly, KS frequently coincides with verbal deficits, and TS with visual–spatial impairments. Though

In this special issue of the American Journal of Medical Genetics Part C, we focus on the "State of Congenital Heart Disease." We anticipate that after viewing this journal, the reader will be up-to-date on the epidemiology of congenital heart disease (CHD), the genetic basis of CHD, ethical concerns, and the global impact of CHD. And most importantly, we are confident that this special issue conveys

In 2014, an extensive review discussing the major steps of cardiac development focusing on growth, formation of primary and chamber myocardium and the development of the cardiac electrical system, was published. Molecular genetic lineage analyses have since furthered our insight in the developmental origin of the various component parts of the heart, which currently can be unambiguously identified

Congenital heart disease (CHD) is common, costly, and critical. Approximately half of all infant deaths due to congenital anomalies are associated with CHD or neural tube defects. As infant mortality improves due to better infection control and peripartum care, congenital anomalies are becoming a key driver of pediatric survival and health. Improving CHD prevention and care globally will play a significant

The etiology of congenital heart disease (CHD) is multifactorial. The birth prevalence of CHD is shaped by a wide variety of maternal, fetal, and neonatal risk factors, along with the rates of prenatal diagnosis and terminations of pregnancy, all of which have geographic variability Epidemiology data availability from low-and-middle-income countries (LMIC) on CHD prevalence, morbidity, and mortality

Congenital heart disease (CHD) in low-and-middle income countries (LMIC) is often characterized by late presentation resulting from inadequate screening and healthcare access in these regions. Accurate estimates of the burden of CHD among school children are often lacking. The objective of this study was to determine the prevalence and distribution of CHD among school children in two communities (urban

The frequent occurrence of congenital heart defects (CHDs) in chromosome abnormality syndromes is well-known, and among aneuploidy syndromes, distinctive patterns have been delineated. We update the type and frequency of CHDs in the aneuploidy syndromes involving trisomy 13, 18, 21, and 22, and in several sex chromosome abnormalities (Turner syndrome, trisomy X, Klinefelter syndrome, 47,XYY, and 48

The 22q11.2 deletion syndrome has an estimated prevalence of 1 in 4-6,000 livebirths. The phenotype varies widely; the most common features include: facial dysmorphia, hypocalcemia, palate and speech disorders, feeding and gastrointestinal disorders, immunodeficiency, recurrent infections, neurodevelopmental and psychiatric disorders, and congenital heart disease. Approximately 60-80% of patients have

Noonan syndrome is a pleomorphic genetic disorder, in which a high percentage of affected individuals have cardiovascular involvement, most prevalently various forms of congenital heart disease (i.e., pulmonary valve stenosis, septal defects, left-sided lesions, and complex forms with multiple anomalies). Care includes attentiveness to several comorbidities, some directly impacting cardiac management

CHARGE syndrome is characterized by a pattern of congenital anomalies (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth, Genital abnormalities, and Ear abnormalities). De novo mutations of chromodomain helicase DNA binding protein 7 (CHD7) are the primary cause of CHARGE syndrome. The clinical phenotype is highly variable including a wide spectrum of congenital heart

Congenital heart defect is one of the most common structural birth defects in the human population. It is highly associated with heterotaxy, a birth defect involving randomized left-right patterning of visceral organ situs. Large scale mouse forward genetics have led to the finding of a central role for cilia in CHD pathogenesis, with some cilia and non-cilia mutations causing CHD with heterotaxy.

The genetic mechanisms underlying congenital heart disease (CHD) are complex and remain incompletely understood. The majority of patients with CHD have an isolated heart defect without other organ system involvement, but the genetic basis of isolated CHD has been even more difficult to elucidate compared to syndromic CHD. Our understanding of the genetics of isolated CHD is advancing in large part

Congenital heart disease (CHD) is the common birth defect worldwide. Despite its recognized burden on public health, the etiology in the vast majority of individuals remains unknown. Chromosomal abnormality plays an important role, frequently observed as large cytogenetically visible rearrangement or small submicroscopic structural variation in the genome. Several genomic disorders are now recognized

Pediatric cardiomyopathies can be caused by variants in genes encoding the sarcomere and cytoskeleton in cardiomyocytes. Variants are typically inherited in an autosomal dominant manner with variable expressivity. De novo variants have been reported, however their overall frequency is largely unknown. We sought to determine the rate of de novo, pathogenic and likely pathogenic (P/LP) variants in children

Sudden cardiac death (SCD) is one of the leading causes of mortality in the U.S. military and competitive athletes. In this study, we simulate how genetic screening may be implemented in the military to prevent an SCD endpoint resulting from hypertrophic cardiomyopathy (HCM). We created a logistic regression model to predict variant pathogenicity in the most common HCM associated genes MYH7 and MYBPC3

PRDM16 (positive regulatory domain 16) is localized in the critical region for cardiomyopathy in patients with deletions of chromosome 1p36, as defined by Gajecka et al., American Journal of Medical Genetics, 2010, 152A, 3074-3083, and encodes a zinc finger transcription factor. We present the first fetal case of left ventricular non-compaction (LVNC) with a PRDM16 variant. The third-trimester obstetric

Aortopathies encompass a variety of inherited and acquired pathologies that increase risk of life-threatening dissection or rupture. Identifying individuals with hereditary thoracic aortic aneurysm and dissection (HTAAD) for longitudinal monitoring, medical therapy, or elective and preventative repair is paramount to reduce risk of cardiovascular-related mortality and complications from dissection

Congenital heart disease (CHD) remains the most common birth defect, with an estimated incidence of approximately 1% of all births. The population of adults with CHD is growing rapidly with advances in medical care. Overall survival to adulthood in the current era estimated to exceed 90%. Genetic causes of CHD can be classified into several broad categories: (a) chromosomal aneuploidy, (b) large chromosomal

Comorbidity of holoprosencephaly (HPE) and congenital heart disease (CHD) in individuals with genetic variants in known HPE-related genes has been recurrently observed. Morphogenesis of the brain and heart from very early stages are regulated by several biological pathways, some of them involved in both heart and brain development as evidenced by genetic studies on model organisms. For instance, downregulation

Genetic association studies in rheumatic heart disease (RHD) have the potential to contribute toward our understanding of the pathogenetic mechanism, and may shed light on controversies about RHD etiology. Furthermore, genetic association studies may uncover biomarkers that can be used to identify susceptible individuals, and contribute toward developing vaccine and novel therapeutic targets. Genetic

Congenital heart disease (CHD) is the most prevalent birth defect and is the result of multiple etiologies including genetic and environmental causes. This article reviews the genetic workup for structural CHD in the clinical setting, beginning with CHD epidemiology and etiology and then moving to genetic testing, clinical evaluation, and genetic counseling. An algorithm is presented as a guide to

Medical and surgical approaches to children with trisomy 13 and 18 are evolving, and an increasing number of patients are being considered for simple and complex cardiac procedures. This review describes how the shifts in medical and social considerations for children with trisomy 13 and 18 mirror the shifts that occurred 50 years ago for children with trisomy 21. Yet the variability in cardiac lesions

PTEN is a dual‐specificity phosphatase and well‐known tumor suppressor gene. When functioning properly, it works in its canonical pathway to inhibit AKT/mTOR and MAPK signaling, leading to cell death and growth regulation. PTEN mutations cause dysregulation of these pathways, resulting in cellular proliferation and overgrowth. When germline mutations are present as in patients with PTEN Hamartoma Tumor

Perlman syndrome is a rare autosomal recessively inherited congenital overgrowth syndrome characterized by polyhydramnios, macrosomia, characteristic facial dysmorphology, renal dysplasia and nephroblastomatosis and multiple congenital anomalies. Perlman syndrome is associated with high neonatal mortality and, survivors have developmental delay and a high risk of Wilms tumor. Recently a Perlman syndrome

Human growth is a complex process starting at conception and completing in adolescence at the time of growth plate fusion. Growth can be divided into four phases: (1) fetal, where the predominant endocrine factors controlling growth are insulin and the insulin‐like growth factors. (2) Infancy, where growth is mainly dependent upon nutrition. (3) Childhood, where the growth hormone–insulin‐like growth

The most common sex chromosome aneuploidies (SCA) (47, XXY; 47, XYY; 47, XXX) frequently result in a milder phenotype than autosomal aneuploidies. Nevertheless, these conditions are highly variable and more symptomatic phenotypes may require significant clinical involvement, including specialty care. While historically most individuals with mild phenotypes remained undiagnosed during their lifetime

Sex chromosome aneuploidies (SCA) are relatively common as a group, perhaps 1 per 500 births, but much more common at conception. Many syndromes have been noted in those with these conditions, but not so many data are available concerning the hypothalamic–pituitary–gonadal (HPG) axis. The physiology of the HPG axis is first reviewed at four epochs in time: fetal, birth and mini‐puberty, childhood,

This introduction to the special issue of AJMG Part C: Overgrowth Syndromes updates the current understanding of overgrowth syndromes. We clarify the terminology associated with overgrowth, review some common pathways to overgrowth and present a preliminary classification based on currently known genomic and epigenetic mechanisms. We introduce the articles of this issue-new research and reviews of

We describe an overgrowth condition associated with X-linked copy number variation. Three brothers displayed an overgrowth pattern at birth that continued postnatally. Clinical findings included macrocephaly, distinctive facial features, developmental delay and variable clubfoot. Normal fetal growth was noted until the third trimester by Hadlock standards, revealing a late gestational overgrowth pattern

The nucleosome remodeling and deacetylase (NuRD) complex is a major regulator of gene expression involved in pluripotency, lineage commitment, and corticogenesis. This important complex is composed of seven different proteins, with mutations in CHD3, CHD4, and GATAD2B being associated with neurodevelopmental disorders presenting with macrocephaly and intellectual disability similar to other overgrowth

The Polycomb repressive complex 2 is an epigenetic writer and recruiter with a role in transcriptional silencing. Constitutional pathogenic variants in its component proteins have been found to cause two established overgrowth syndromes: Weaver syndrome (EZH2-related overgrowth) and Cohen-Gibson syndrome (EED-related overgrowth). Imagawa et al. (2017) initially reported a singleton female with a Weaver-like