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Since the introduction of next-generation sequencing, an increasing number of disorders have been discovered to have genetic etiology. To address diverse clinical questions and coordinate research activities that arise with the identification of these rare disorders, we developed the Human Disease Genes website series (HDG website series): an international digital library that records detailed information on the clinical phenotype of novel genetic variants in the human genome (https://humandiseasegenes.info/). Each gene website is moderated by a dedicated team of clinicians and researchers, focused on specific genes, and provides up-to-date-including unpublished-clinical information. The HDG website series is expanding rapidly with 424 genes currently adopted by 325 moderators from across the globe. On average, a gene website has detailed phenotypic information of 14.4 patients. There are multiple examples of added value, one being the ARID1B gene website, which was recently utilized in research to collect clinical information of 81 new patients. Additionally, several gene websites have more data available than currently published in the literature. In conclusion, the HDG website series provides an easily accessible, open and up-to-date clinical data resource for patients with pathogenic variants of individual genes. This is a valuable resource not only for clinicians dealing with rare genetic disorders such as developmental delay and autism, but other professionals working in diagnostics and basic research. Since the HDG website series is a dynamic platform, its data also include the phenotype of yet unpublished patients curated by professionals providing higher quality clinical detail to improve management of these rare disorders., (© 2021 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

We report on 19 individuals with a recurrent de novo c.607C>T mutation in PACS1. This specific mutation gives rise to a recognizable intellectual disability syndrome. There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual "wavy" profile, flat philtrum, and diastema of the teeth. Intellectual disability, ranging from mild to moderate, was present in all. Hypotonia is common in infancy (8/19). Seizures are frequent (12/19) and respond well to anticonvulsive medication. Structural malformations are common, including heart (10/19), brain (12/16), eye (10/19), kidney (3/19), and cryptorchidism (6/12 males). Feeding dysfunction is presenting in infancy with failure to thrive (5/19), gastroesophageal reflux (6/19), and gastrostomy tube placement (4/19). There is persistence of oral motor dysfunction. We provide suggestions for clinical work-up and management and hope that the present study will facilitate clinical recognition of further cases., (© 2016 Wiley Periodicals, Inc.)

Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease that is the most frequent monogenic cause of end-stage renal disease in children. Infantile NPHP, often in combination with other features like situs inversus, are commonly caused by mutations in the INVS gene. INVS encodes the ciliary protein inversin, and mutations induce dysfunction of the primary cilia. In this article, we present a family with two severely affected fetuses that were aborted after discovery of grossly enlarged cystic kidneys by ultrasonography before 22 weeks gestation. Exome sequencing showed that the fetuses were homozygous for a previously unreported nonsense mutation, resulting in a truncation in the IQ1 domain of inversin. This mutation induces nonsense-mediated RNA decay, as suggested by a reduced RNA level in fibroblasts derived from the fetus. However, a significant amount of mutant INVS RNA was present in these fibroblasts, yielding mutant inversin protein that was mislocalized. In control fibroblasts, inversin was present in the ciliary axoneme as well as at the basal body, whereas in the fibroblasts from the fetus, inversin could only be detected at the basal body. The phenotype of both fetuses is partly characteristic of infantile NPHP and Potter sequence. We also identified that the fetuses had mild skeletal abnormalities, including shortening and bowing of long bones, which may expand the phenotypic spectrum associated with INVS mutations., (© 2014 Wiley Periodicals, Inc.)

Meier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by primordial dwarfism, microtia, and patellar aplasia/hypoplasia. Recently, mutations in the ORC1, ORC4, ORC6, CDT1, and CDC6 genes, encoding components of the pre-replication complex, have been identified. This complex is essential for DNA replication and therefore mutations are expected to impair cell proliferation and consequently could globally reduce growth. However, detailed growth characteristics of MGS patients have not been reported, and so this is addressed here through study of 45 MGS patients, the largest cohort worldwide. Here, we report that growth velocity (length) is impaired in MGS during pregnancy and first year of life, but, thereafter, height increases in paralleled normal reference centiles, resulting in a mean adult height of -4.5 standard deviations (SD). Height is dependent on ethnic background and underlying molecular cause, with ORC1 and ORC4 mutations causing more severe short stature and microcephaly. Growth hormone therapy (n = 9) was generally ineffective, though in two patients with significantly reduced IGF1 levels, growth was substantially improved by GH treatment, with 2SD and 3.8 SD improvement in height. Growth parameters for monitoring growth in future MGS patients are provided and as well we highlight that growth is disproportionately affected in certain structures, with growth related minor genital abnormalities (42%) and mammary hypoplasia (100%) frequently present, in addition to established effects on ears and patellar growth., (Copyright © 2012 Wiley Periodicals, Inc.)

Hyperphosphatasia with neurologic deficit (Mabry syndrome) was first described in a single family (OMIM#239300) by Mabry et al. [1970]. Although considered rare at the time, more than 20 individuals with the triad of developmental disability, seizures, and hyperphosphatasia have been identified world-wide. The 1-6 mannosyltransferase 2, phosphatidylinositol glycan V (PIGV) gene has been found to be disrupted in some patients with the additional feature of brachytelephalangy. In the present report we identify three patients compound homozygous for PIGV mutations. Two siblings were found to be compound heterozygotes for c.467G > A and c.494C > A in exon 3 of PIGV (the c.494C > A PIGV variant is novel). A third patient with similar phenotype, was a compound heterozygote for the known c.1022C > A/c.1022C > T (p.Ala341Glu/p.Ala341Val) mutation. This patient was also noted to have lysosomal storage in cultured fibroblasts. In contrast, the fourth patient who had no apparent hand abnormality, was found to be heterozygous for a previously unclassified c.1369C > T mutation in exon 4 of the PIGV gene, resulting in a p.Leu457Phe substitution in the catalytic domain of the enzyme. Unless this variant has a dominant negative effect, however, it seems likely that another GPI biosynthesis gene variant may contribute to the disorder, possibly through digenic inheritance. Since slightly fewer than half of the nine cases presented in this report and our previous report [Thompson et al., 2010] have PIGV mutations, we suggest that other genes critical to GPI anchor biosynthesis are likely to be disrupted in some patients., (Copyright © 2012 Wiley Periodicals, Inc.)

We used exome sequencing of blood DNA in four unrelated patients to identify the genetic basis of metaphyseal chondromatosis with urinary excretion of D-2-hydroxy-glutaric acid (MC-HGA), a rare entity comprising severe chondrodysplasia, organic aciduria, and variable cerebral involvement. No evidence for recessive mutations was found; instead, two patients showed mutations in IDH1 predicting p.R132H and p.R132S as apparent somatic mosaicism. Sanger sequencing confirmed the presence of the mutation in blood DNA in one patient, and in blood and saliva (but not in fibroblast) DNA in the other patient. Mutations at codon 132 of IDH1 change the enzymatic specificity of the cytoplasmic isocitrate dehydrogenase enzyme. They result in increased D-2-hydroxy-glutarate production, α-ketoglutarate depletion, activation of HIF-1α (a key regulator of chondrocyte proliferation at the growth plate), and reduction of N-acetyl-aspartyl-glutamate level in glial cells. Thus, somatic mutations in IDH1 may explain all features of MC-HGA, including sporadic occurrence, metaphyseal disorganization, and chondromatosis, urinary excretion of D-2-hydroxy-glutaric acid, and reduced cerebral myelinization., (Copyright © 2011 Wiley Periodicals, Inc.)

CHARGE syndrome is an autosomal dominant condition that is caused by mutations in the CHD7 gene. Few familial cases of this syndrome have been reported and these were characterized by a wide clinical variability. We here report on five CHD7 mutation positive families and comment on their clinical features. We observed somatic and germline mosaicism as well as parent-to-child transmission of non-mosaic CHD7 mutations as causes of familial CHARGE syndrome. In one family with two affected sibs a somatic mutation was identified in lymphocytes of a clinically unaffected parent (2520G > A in exon 8). This is the second report of somatic CHD7 mosaicism in an unaffected parent. In two further families with affected siblings, we could not detect the mutation in parental lymphocytes suggesting germline mosaicism. The previously reported clinical variability was strikingly present in all five families. We find that alterations in CHD7 can result in a very mild phenotype, characterized by only a few minor symptoms of the CHARGE syndrome clinical spectrum. Such a mild phenotype was present in two families that shared the same 6322G > A missense mutation. These two families showed parent-to-child transmission. Phenotypically milder forms of CHARGE syndrome have a higher risk of transmission to multiple family members., ((c) 2007 Wiley-Liss, Inc.)

Myosin XVA is an unconventional myosin which has been implicated in autosomal recessive nonsyndromic hearing impairment (ARNSHI) in humans. In Myo15A mouse models, vestibular dysfunction accompanies the autosomal recessive hearing loss. Genomewide homozygosity mapping and subsequent fine mapping in two Turkish families with ARNSHI revealed significant linkage to a critical interval harboring a known deafness gene MYO15A on chromosome 17p13.1-17q11.2. Subsequent sequencing of the MYO15A gene led to the identification of a novel missense mutation, c.5492G-->T (p.Gly1831Val) and a novel splice site mutation, c.8968-1G-->C. These mutations were not detected in additional 64 unrelated ARNSHI index patients and in 230 Turkish control chromosomes. Gly1831 is a conserved residue located in the motor domains of the different classes of myosins of different species. Molecular modeling of the motor head domain of the human myosin XVa protein suggests that the Gly1831Val mutation inhibits the powerstroke by reducing backbone flexibility and weakening the hydrophobic interactions necessary for signal transmission to the converter domain., (Copyright (c) 2007 Wiley-Liss, Inc.)

Partial deletions of the long arm of chromosome 18 lead to variable phenotypes. Common clinical features include a characteristic face, short stature, congenital aural atresia (CAA), abnormalities of the feet, and mental retardation (MR). The presence or absence of these clinical features may depend on the size and position of the deleted region. Conversely, it is also known that patients whose breakpoints are localized within the same chromosome band may exhibit distinct phenotypes. New molecular techniques such as array CGH allow for a more precise determination of breakpoints in cytogenetic syndromes, thus leading to better-defined genotype-phenotype correlations. In order to update the phenotypic map for chromosome 18q deletions, we applied a tiling resolution chromosome 18 array to determine the exact breakpoints in 29 patients with such deletions. Subsequently, we linked the genotype to the patient's phenotype and integrated our results with those previously published. Using this approach, we were able to refine the critical regions for microcephaly (18q21.33), short stature (18q12.1-q12.3, 18q21.1-q21.33, and 18q22.3-q23), white matter disorders and delayed myelination (18q22.3-q23), growth hormone insufficiency (18q22.3-q23), and CAA (18q22.3). Additionally, the overall level of MR appeared to be mild in patients with deletions distal to 18q21.33 and severe in patients with deletions proximal to 18q21.31. The critical region for the 'typical' 18q-phenotype is a region of 4.3 Mb located within 18q22.3-q23. Molecular characterization of more patients will ultimately lead to a further delineation of the critical regions and thus to the identification of candidate genes for these specific traits., ((c) 2007 Wiley-Liss, Inc.)

Heterozygous mutations in the transcription factor gene p63 cause at least six different syndromes with various combinations of ectodermal dysplasia, orofacial clefting and limb malformations. Here we will present an update of mutations in the p63 gene together with a comprehensive overview of the associated clinical features in 227 patients. These data confirm the previously recognized genotype-phenotype associations. Moreover, we report that there is a large degree of clinical variability in each of the p63-associated disorders. This is illustrated by the different phenotypes that are seen for the five-hotspot mutations that explain almost 90% of all EEC syndrome patients., ((c) 2006 Wiley-Liss, Inc.)

We describe three patients with Malpuech syndrome from two families. Previously, 10 patients from 6 families have been reported. Consanguinity in two families suggests autosomal recessive inheritance. Growth retardation, mental retardation, cleft lip, and/or palate, hypertelorism, urogenital abnormalities, and caudal appendage are the key features. Although the spectrum of the features in the reported patients is variable, we do think this syndrome represents a distinct entity. Chromosomal anomalies should be carefully searched for. We discuss differential diagnosis and possible candidate genes and propose diagnostic criteria for Malpuech syndrome., (2005 Wiley-Liss, Inc.)

We report on seven patients affected with Nevo syndrome, a rare, autosomal recessive disorder characterized by increased perinatal length, kyphosis, muscular hypotonia, and joint laxity. Since its first description by Nevo et al. [1974], only a few cases have been reported. Because some of these patients present clinical features similar to those of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA), an inherited connective tissue disorder characterized by a deficiency of lysyl hydroxylase due to mutations in PLOD1, we studied seven patients with Nevo syndrome, three of whom have previously been reported, and four of whom are new. In the five patients from whom urine was available, the ratio of total urinary lysyl pyridinoline (LP) to hydroxylysyl pyridinoline (HP) was elevated (8.2, 7.8, 8.6, 3.5, and 4.8, respectively) compared with that in controls (0.20 +/- 0.05, range 0.10-0.38), and similar to that observed in patients with EDS VIA (5.97 +/- 0.99, range 4.3-8.1). Six patients were homozygous for a point mutation in exon 9 of PLOD1 causing a p.R319X nonsense mutation, while one patient was homozygous for a large deletion comprising exon 17 of PLOD1. We conclude that the Nevo syndrome is allelic to and clinically indistinguishable from EDS VIA, and present evidence that increased length at birth and wristdrop, in addition to muscular hypotonia and kyphoscoliosis, should prompt the physician to consider EDS VIA earlier than heretofore., ((c) 2005 Wiley-Liss, Inc.)

Feingold syndrome is characterized by autosomal dominant inheritance of microcephaly and limb malformations, notably hypoplastic thumbs, and clinodactyly of second and fifth fingers. Syndactyly frequently involves the second and third, as well as the fourth and fifth toes. Approximately one in three Feingold syndrome patients have esophageal or duodenal atresia or both. Anal atresia has been reported in a single case. At least 79 patients in 25 families have been reported. The syndrome has autosomal dominant inheritance with full penetrance, and variable expressivity. Vertebral anomalies, cardiac malformations, and deafness have been noted in a minority of patients. Here, we report a patient with hydronephrosis of one kidney and cystic dysplasia of the other, necessitating nephrectomy. The overall pattern of malformations in Feingold syndrome shows considerable overlap with the VATER/VACTERL association. The gene for Feingold syndrome maps to 2p23-p24, but remains to be identified. Comparison of the pattern of anomalies that occurs in the Feingold syndrome in humans and malformations that are present in mice with mutations of genes in the sonic hedgehog signaling pathway suggest, that the elusive Feingold syndrome gene may involve this signaling pathway as well., (Copyright 2003 Wiley-Liss, Inc.)