Kidney Disease Associated With Mono-allelic COL4A3 and COL4A4 Variants: A Case Series of 17 Families.

Rationale & Objective: Mono-allelic variants in COL4A3 and COL4A4 (COL4A3/COL4A4) have been identified in a spectrum of glomerular basement membrane nephropathies, including thin basement membrane nephropathy and autosomal dominant Alport syndrome. With the increasing use of next generation sequencing, mono-allelic COL4A3/COL4A4 variants are detected more frequently, but phenotypic heterogeneity impedes counseling. We aimed to investigate the phenotypic spectrum, kidney biopsy results, and segregation patterns of patients with mono-allelic COL4A3/COL4A4 variants identified by whole exome sequencing. Study Design: Case series. Setting & Participants: We evaluated clinical and pathologic characteristics of 17 Dutch index patients with mono-allelic variants in COL4A3/COL4A4 detected by diagnostic whole exome sequencing and 25 affected family members with variants confirmed by Sanger sequencing. Results: Eight different mono-allelic COL4A3/COL4A4 variants were identified across members of 11 families, comprising 7 glycine substituted missense variants and 1 frameshift variant. All index patients had microscopic hematuria at clinical presentation (median age 43 years) and 14 had (micro)albuminuria/proteinuria. All family members showed co-segregation of the variant with at least hematuria. At end of follow-up of all 42 individuals (median age 54 years), 16/42 patients had kidney function impairment, of whom 6 had kidney failure. Reports of kidney biopsies of 14 patients described thin basement membrane nephropathy, focal segmental glomerulosclerosis, minimal change lesions, and Alport syndrome. Electron microscopy images of 7 patients showed a significantly thinner glomerular basement membrane compared with images of patients with idiopathic focal segmental glomerulosclerosis and other hereditary glomerular diseases. No genotype-phenotype correlations could be established. Limitations: Retrospective design, ascertainment bias toward severe kidney phenotypes, and familial hematuria. Conclusions: This study confirms the wide phenotypic spectrum associated with mono-allelic COL4A3/COL4A4 variants, extending from isolated microscopic hematuria to kidney failure with high intra- and interfamilial variability.

Diagnostic exome sequencing in 100 consecutive patients with both epilepsy and intellectual disability.

OBJECTIVE: Epilepsy is highly prevalent among patients with intellectual disability (ID), and seizure control is often difficult. Identification of the underlying etiology in this patient group is important for daily clinical care. We assessed the diagnostic yield of whole exome sequencing (WES). In addition, we evaluated which clinical characteristics influence the likelihood of identifying a genetic cause and we assessed the potential impact of the genetic diagnosis on (antiepileptic) treatment strategy. METHODS: One hundred patients with both unexplained epilepsy and (borderline) ID (intelligence quotient ≤ 85) were included. All patients were evaluated by a clinical geneticist, a (pediatric) neurologist, and/or a specialist ID physician. WES analysis was performed in two steps. In step 1, analysis was restricted to the latest versions of ID and/or epilepsy gene panels. In step 2, exome analysis was extended to all genes (so-called full exome analysis). The results were classified according to the American College of Medical Genetics and Genomics guidelines. RESULTS: In 58 patients, the diagnostic WES analysis reported one or more variant(s). In 25 of the 100 patients, these were classified as (likely) pathogenic, in 24 patients as variants of uncertain significance, and in the remaining patients the variant was most likely not related to the phenotype. In 10 of 25 patients (40%) with a (likely) pathogenic variant, the genetic diagnosis might have an impact on the treatment strategy in the future. SIGNIFICANCE: This study illustrates the clinical diagnostic relevance of WES for patients with both epilepsy and ID. It also demonstrates that implementing WES diagnostics might have impact on the (antiepileptic) treatment strategy in this population. Confirmation of variants of uncertain significance in (candidate) genes may further increase the yield.

A Novel Hypokalemic-Alkalotic Salt-Losing Tubulopathy in Patients with CLDN10 Mutations.

Mice lacking distal tubular expression of CLDN10, the gene encoding the tight junction protein Claudin-10, show enhanced paracellular magnesium and calcium permeability and reduced sodium permeability in the thick ascending limb (TAL), leading to a urine concentrating defect. However, the function of renal Claudin-10 in humans remains undetermined. We identified and characterized CLDN10 mutations in two patients with a hypokalemic-alkalotic salt-losing nephropathy. The first patient was diagnosed with Bartter syndrome (BS) >30 years ago. At re-evaluation, we observed hypocalciuria and hypercalcemia, suggesting Gitelman syndrome (GS). However, serum magnesium was in the upper normal to hypermagnesemic range, thiazide responsiveness was not blunted, and genetic analyses did not show mutations in genes associated with GS or BS. Whole-exome sequencing revealed compound heterozygous CLDN10 sequence variants [c.446C>G (p.Pro149Arg) and c.465-1G>A (p.Glu157_Tyr192del)]. The patient had reduced urinary concentrating ability, with a preserved aquaporin-2 response to desmopressin and an intact response to furosemide. These findings were not in line with any other known salt-losing nephropathy. Subsequently, we identified a second unrelated patient showing a similar phenotype, in whom we detected compound heterozygous CLDN10 sequence variants [c.446C>G (p.(Pro149Arg) and c.217G>A (p.Asp73Asn)]. Cell surface biotinylation and immunofluorescence experiments in cells expressing the encoded mutants showed that only one mutation caused significant differences in Claudin-10 membrane localization and tight junction strand formation, indicating that these alterations do not fully explain the phenotype. These data suggest that pathogenic CLDN10 mutations affect TAL paracellular ion transport and cause a novel tight junction disease characterized by a non-BS, non-GS autosomal recessive hypokalemic-alkalotic salt-losing phenotype.

Refining the Diagnosis of Congenital Nephrotic Syndrome on Long-term Stored Tissue: c.1097G>A (p.(Arg366His)) WT1 Mutation Causing Denys Drash Syndrome.

Congenital nephrotic syndrome (CNS) caused by a mutation in the Wilms tumor 1 suppressor gene (WT1) is part of Denys Drash Syndrome or Frasier syndrome. In the framework of genetic counseling, the diagnosis of CNS can be refined with gene mutation studies on long-term stored formalin-fixed paraffin-embedded tissue from postmortem examination. We report a case of diffuse mesangial sclerosis with perinatal death caused by a de novo mutation in the WT1 gene in a girl with an XY-genotype. This is the first case of Denys Drash Syndrome with the uncommon missense c.1097G>A [p.(Arg366His)] mutation in the WT1 gene which has been diagnosed on long-term stored formalin-fixed paraffin-embedded tissue in 1993. This emphasizes the importance of retained and adequately stored tissue as a resource in the ongoing medical care and counseling.

De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome.

Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5' end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1(st) coding exon), c.16A>T (p.Lys6(∗)) and c.35_38delTCAA (p.Ile12Lysfs(∗)4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5' end of the geminin protein. All three GMNN mutations identified alter sites 5' to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS.

Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2.

Linkage analysis combined with whole-exome sequencing in a large family with congenital and stable non-syndromic unilateral and asymmetric hearing loss (NS-UHL/AHL) revealed a heterozygous truncating mutation, c.286_303delinsT (p.Ser96Ter), in KITLG. This mutation co-segregated with NS-UHL/AHL as a dominant trait with reduced penetrance. By screening a panel of probands with NS-UHL/AHL, we found an additional mutation, c.200_202del (p.His67_Cys68delinsArg). In vitro studies revealed that the p.His67_Cys68delinsArg transmembrane isoform of KITLG is not detectable at the cell membrane, supporting pathogenicity. KITLG encodes a ligand for the KIT receptor. Also, KITLG-KIT signaling and MITF are suggested to mutually interact in melanocyte development. Because mutations in MITF are causative of Waardenburg syndrome type 2 (WS2), we screened KITLG in suspected WS2-affected probands. A heterozygous missense mutation, c.310C>G (p.Leu104Val), that segregated with WS2 was identified in a small family. In vitro studies revealed that the p.Leu104Val transmembrane isoform of KITLG is located at the cell membrane, as is wild-type KITLG. However, in culture media of transfected cells, the p.Leu104Val soluble isoform of KITLG was reduced, and no soluble p.His67_Cys68delinsArg and p.Ser96Ter KITLG could be detected. These data suggest that mutations in KITLG associated with NS-UHL/AHL have a loss-of-function effect. We speculate that the mechanism of the mutation underlying WS2 and leading to membrane incorporation and reduced secretion of KITLG occurs via a dominant-negative or gain-of-function effect. Our study unveils different phenotypes associated with KITLG, previously associated with pigmentation abnormalities, and will thereby improve the genetic counseling given to individuals with KITLG variants.

Meier-Gorlin syndrome.

Meier-Gorlin syndrome (MGS) is a rare autosomal recessive primordial dwarfism disorder, characterized by microtia, patellar applasia/hypoplasia, and a proportionate short stature. Associated clinical features encompass feeding problems, congenital pulmonary emphysema, mammary hypoplasia in females and urogenital anomalies, such as cryptorchidism and hypoplastic labia minora and majora. Typical facial characteristics during childhood comprise a small mouth with full lips and micro-retrognathia. During ageing, a narrow, convex nose becomes more prominent. The diagnosis MGS should be considered in patients with at least two of the three features of the clinical triad of microtia, patellar anomalies, and pre- and postnatal growth retardation. In patients with short stature and/or microtia, the patellae should be assessed with care by ultrasonography before age 6 or radiography thereafter. Mutations in one of five genes (ORC1, ORC4, ORC6, CDT1, and CDC6) of the pre-replication complex, involved in DNA-replication, are detected in approximately 67-78% of patients with MGS. Patients with ORC1 and ORC4 mutations appear to have the most severe short stature and microcephaly. Management should be directed towards in-depth investigation, treatment and prevention of associated problems, such as growth retardation, feeding problems, hearing loss, luxating patellae, knee pain, gonarthrosis, and possible pulmonary complications due to congenital pulmonary emphysema with or without broncho- or laryngomalacia. Growth hormone treatment is ineffective in most patients with MGS, but may be effective in patients in whom growth continues to decrease after the first year of life (usually growth velocity normalizes after the first year) and with low levels of IGF1. At present, few data is available about reproduction of females with MGS, but the risk of premature labor might be increased. Here, we propose experience-based guidelines for the regular care and treatment of MGS patients.

Definition of 5q11.2 microdeletion syndrome reveals overlap with CHARGE syndrome and 22q11 deletion syndrome phenotypes.

Microdeletions of the 5q11.2 region are rare; in literature only two patients with a deletion in this region have been reported so far. In this study, we describe four additional patients and further define this new 5q11.2 microdeletion syndrome. A comparison of the features observed in all six patients with overlapping 5q11.2 deletions showed a phenotypic spectrum that overlaps with CHARGE syndrome and 22q11.2 deletion syndrome including choanal atresia, developmental delay, heart defects, external ear abnormalities, and short stature. No colobomas or abnormalities of semicircular canals and olfactory nerves were reported. Two male patients had genital abnormalities. We estimated a 2.0 Mb (53.0-55.0 Mb) Shortest Region of Overlap (SRO) for the main clinical characteristics of the syndrome. This region contains nine genes and two non-coding microRNAs. In this region DHX29 serves as the candidate gene as it encodes an ATP-dependent RNA-helicase that is involved in the initiation of RNA translation. Screening a small cohort of 14 patients who presented the main features, however, did not reveal any pathogenic abnormalities of DHX29.

A de novo non-sense mutation in ZBTB18 in a patient with features of the 1q43q44 microdeletion syndrome.

The phenotype of patients with a chromosome 1q43q44 microdeletion (OMIM; 612337) is characterized by intellectual disability with no or very limited speech, microcephaly, growth retardation, a recognizable facial phenotype, seizures, and agenesis of the corpus callosum. Comparison of patients with different microdeletions has previously identified ZBTB18 (ZNF238) as a candidate gene for the 1q43q44 microdeletion syndrome. Mutations in this gene have not yet been described. We performed exome sequencing in a patient with features of the 1q43q44 microdeletion syndrome that included short stature, microcephaly, global developmental delay, pronounced speech delay, and dysmorphic facial features. A single de novo non-sense mutation was detected, which was located in ZBTB18. This finding is consistent with an important role for haploinsufficiency of ZBTB18 in the phenotype of chromosome 1q43q44 microdeletions. The corpus callosum is abnormal in mice with a brain-specific knock-out of ZBTB18. Similarly, most (but not all) patients with the 1q43q44 microdeletion syndrome have agenesis or hypoplasia of the corpus callosum. In contrast, the patient with a ZBTB18 point mutation reported here had a structurally normal corpus callosum on brain MRI. Incomplete penetrance or haploinsufficiency of other genes from the critical region may explain the absence of corpus callosum agenesis in this patient with a ZBTB18 point mutation. The findings in this patient with a mutation in ZBTB18 will contribute to our understanding of the 1q43q44 microdeletion syndrome.

The phenotype of Floating-Harbor syndrome: clinical characterization of 52 individuals with mutations in exon 34 of SRCAP.

BACKGROUND: Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease-causing. With the availability of a DNA based confirmatory test, we set forth to define the clinical features of this syndrome. METHODS AND RESULTS: Clinical information on fifty-two individuals with SRCAP mutations was collected using standardized questionnaires. Twenty-four males and twenty-eight females were studied with ages ranging from 2 to 52 years. The facial phenotype and expressive language impairments were defining features within the group. Height measurements were typically between minus two and minus four standard deviations, with occipitofrontal circumferences usually within the average range. Thirty-three of the subjects (63%) had at least one major anomaly requiring medical intervention. We did not observe any specific phenotype-genotype correlations. CONCLUSIONS: This large cohort of individuals with molecularly confirmed FHS has allowed us to better delineate the clinical features of this rare but classic genetic syndrome, thereby facilitating the development of management protocols.

New TRPC6 gain-of-function mutation in a non-consanguineous Dutch family with late-onset focal segmental glomerulosclerosis.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a leading cause of steroid-resistant nephrotic syndrome. Hereditary FSGS is frequently caused by mutations in important structural podocyte proteins, including the slit diaphragm-associated transient receptor potential channel C6 (TRPC6). METHODS: In five patients with biopsy-proven autosomal-dominant FSGS from five different Dutch families, all 13 exons of TRPC6 were sequenced. Upon identification of a novel TRPC6 sequence variant, the resultant amino acid change was introduced in the wild-type TRPC6 protein and functionally tested using patch-clamp analyses and cell-surface biotinylation experiments. RESULTS: None of the previously described TRPC6 mutations were found in our cohort. In one family, we identified a novel c.524G>A sequence variant resulting in a p.Arg175Gln (R175Q) substitution in the TRPC6 protein. This sequence variant was absent in 449 control subjects and from public SNP databases. The mutation was located in the third ankyrin repeat domain (ANK3) in the cytoplasmic N-tail of TRPC6, important for protein-protein interaction and regulation of ion channel activity. Patch-clamp analyses of the mutant channel indeed showed an increased TRPC6 channel-mediated current. However, cell-surface expression of the mutant channel was not increased. CONCLUSIONS: We identified a novel TRPC6 p.Arg175Gln gain-of-function mutation that shows increased TRPC6-mediated current, which is not due to altered cell-surface expression. This is the first mutation identified in ANK3 of the TRPC6 N-tail and is most likely responsible for the late-onset autosomal dominant FSGS in this family.

Meier-Gorlin syndrome: growth and secondary sexual development of a microcephalic primordial dwarfism disorder.

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.

A novel classification system to predict the pathogenic effects of CHD7 missense variants in CHARGE syndrome.

CHARGE syndrome is characterized by the variable occurrence of multisensory impairment, congenital anomalies, and developmental delay, and is caused by heterozygous mutations in the CHD7 gene. Correct interpretation of CHD7 variants is essential for genetic counseling. This is particularly difficult for missense variants because most variants in the CHD7 gene are private and a functional assay is not yet available. We have therefore developed a novel classification system to predict the pathogenic effects of CHD7 missense variants that can be used in a diagnostic setting. Our classification system combines the results from two computational algorithms (PolyPhen-2 and Align-GVGD) and the prediction of a newly developed structural model of the chromo- and helicase domains of CHD7 with segregation and phenotypic data. The combination of different variables will lead to a more confident prediction of pathogenicity than was previously possible. We have used our system to classify 145 CHD7 missense variants. Our data show that pathogenic missense mutations are mainly present in the middle of the CHD7 gene, whereas benign variants are mainly clustered in the 5' and 3' regions. Finally, we show that CHD7 missense mutations are, in general, associated with a milder phenotype than truncating mutations.

Mutation update on the CHD7 gene involved in CHARGE syndrome.

CHD7 is a member of the chromodomain helicase DNA-binding (CHD) protein family that plays a role in transcription regulation by chromatin remodeling. Loss-of-function mutations in CHD7 are known to cause CHARGE syndrome, an autosomal-dominant malformation syndrome in which several organ systems, for example, the central nervous system, eye, ear, nose, and mediastinal organs, are variably involved. In this article, we review all the currently described CHD7 variants, including 183 new pathogenic mutations found by our laboratories. In total, we compiled 528 different pathogenic CHD7 alterations from 508 previously published patients with CHARGE syndrome and 294 unpublished patients analyzed by our laboratories. The mutations are equally distributed along the coding region of CHD7 and most are nonsense or frameshift mutations. Most mutations are unique, but we identified 94 recurrent mutations, predominantly arginine to stop codon mutations. We built a locus-specific database listing all the variants that is easily accessible at www.CHD7.org. In addition, we summarize the latest data on CHD7 expression studies, animal models, and functional studies, and we discuss the latest clinical insights into CHARGE syndrome.

Mutations in DYNC1H1 cause severe intellectual disability with neuronal migration defects.

BACKGROUND: DYNC1H1 encodes the heavy chain protein of the cytoplasmic dynein 1 motor protein complex that plays a key role in retrograde axonal transport in neurons. Furthermore, it interacts with the LIS1 gene of which haploinsufficiency causes a severe neuronal migration disorder in humans, known as classical lissencephaly or Miller-Dieker syndrome. AIM: To describe the clinical spectrum and molecular characteristics of DYNC1H1 mutations. METHODS: A family based exome sequencing approach was used to identify de novo mutations in patients with severe intellectual disability. RESULTS: In this report the identification of two de novo missense mutations in DYNC1H1 (p.Glu1518Lys and p.His3822Pro) in two patients with severe intellectual disability and variable neuronal migration defects is described. CONCLUSION: Since an autosomal dominant mutation in DYNC1H1 was previously identified in a family with the axonal (type 2) form of Charcot- Marie-Tooth (CMT2) disease and mutations in Dync1h1 in mice also cause impaired neuronal migration in addition to neuropathy, these data together suggest that mutations in DYNC1H1 can lead to a broad phenotypic spectrum and confirm the importance of DYNC1H1 in both central and peripheral neuronal functions.

Meier-Gorlin syndrome genotype-phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis.

Meier-Gorlin syndrome (MGS) is an autosomal recessive disorder characterized by microtia, patellar aplasia/hypoplasia, and short stature. Recently, mutations in five genes from the pre-replication complex (ORC1, ORC4, ORC6, CDT1, and CDC6), crucial in cell-cycle progression and growth, were identified in individuals with MGS. Here, we report on genotype-phenotype studies in 45 individuals with MGS (27 females, 18 males; age 3 months-47 years). Thirty-five individuals had biallelic mutations in one of the five causative pre-replication genes. No homozygous or compound heterozygous null mutations were detected. In 10 individuals, no definitive molecular diagnosis was made. The triad of microtia, absent/hypoplastic patellae, and short stature was observed in 82% of individuals with MGS. Additional frequent clinical features were mammary hypoplasia (100%) and abnormal genitalia (42%; predominantly cryptorchidism and hypoplastic labia minora/majora). One individual with ORC1 mutations only had short stature, emphasizing the highly variable clinical spectrum of MGS. Individuals with ORC1 mutations had significantly shorter stature and smaller head circumferences than individuals from other gene categories. Furthermore, compared with homozygous missense mutations, compound heterozygous mutations appeared to have a more severe effect on phenotype, causing more severe growth retardation in ORC4 and more frequently pulmonary emphysema in CDT1. A lethal phenotype was seen in four individuals with compound heterozygous ORC1 and CDT1 mutations. No other clear genotype-phenotype association was observed. Growth hormone and estrogen treatment may be of some benefit, respectively, to growth retardation and breast hypoplasia, though further studies in this patient group are needed.

Novel NCC mutants and functional analysis in a new cohort of patients with Gitelman syndrome.

Gitelman syndrome (GS) is an autosomal recessive disorder characterized by hypokalemic metabolic alkalosis in conjunction with significant hypomagnesemia and hypocalciuria. The GS phenotype is caused by mutations in the solute carrier family 12, member 3 (SLC12A3) gene that encodes the thiazide-sensitive NaCl cotransporter (NCC). We analyzed DNA samples of 163 patients with a clinical suspicion of GS by direct sequencing of all 26 exons of the SLC12A3 gene. In total, 114 different mutations were identified, 31 of which have not been reported before. These novel variants include 3 deletions, 18 missense, 6 splice site and 4 nonsense mutations. We selected seven missense mutations to investigate their effect on NCC activity and plasma membrane localization by using the Xenopus laevis oocyte expression system. The Thr392Ile mutant did not display transport activity (probably class 2 mutation), while the Asn442Ser and Gln1030Arg NCC mutants showed decreased plasma membrane localization and consequently function, likely due to impaired trafficking (class 3 mutation). Even though the NaCl uptake was hampered for NCC mutants Glu121Asp, Pro751Leu, Ser475Cys and Tyr489His, the transporters reached the plasma membrane (class 4 mutation), suggesting an effect on NCC regulation or ion affinity. The present study shows the identification of 38 novel mutations in the SLC12A3 gene and provides insight into the mechanisms that regulate NCC.

Mutations in the pre-replication complex cause Meier-Gorlin syndrome.

Meier-Gorlin syndrome (ear, patella and short-stature syndrome) is an autosomal recessive primordial dwarfism syndrome characterized by absent or hypoplastic patellae and markedly small ears¹â»³. Both pre- and post-natal growth are impaired in this disorder, and although microcephaly is often evident, intellect is usually normal in this syndrome. We report here that individuals with this disorder show marked locus heterogeneity, and we identify mutations in five separate genes: ORC1, ORC4, ORC6, CDT1 and CDC6. All of these genes encode components of the pre-replication complex, implicating defects in replication licensing as the cause of a genetic syndrome with distinct developmental abnormalities.

A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism.

Cerebellar hypoplasia and slowly progressive ophthalmological symptoms are common features in patients with congenital disorders of glycosylation type I. In a group of patients with congenital disorders of glycosylation type I with unknown aetiology, we have previously described a distinct phenotype with severe, early visual impairment and variable eye malformations, including optic nerve hypoplasia, retinal coloboma, congenital cataract and glaucoma. Some of the symptoms overlapped with the phenotype in other congenital disorders of glycosylation type I subtypes, such as vermis hypoplasia, anaemia, ichtyosiform dermatitis, liver dysfunction and coagulation abnormalities. We recently identified pathogenic mutations in the SRD5A3 gene, encoding steroid 5α-reductase type 3, in a group of patients who presented with this particular phenotype and a common metabolic pattern. Here, we report on the clinical, genetic and metabolic features of 12 patients from nine families with cerebellar ataxia and congenital eye malformations diagnosed with SRD5A3-congenital disorders of glycosylation due to steroid 5α-reductase type 3 defect. This enzyme is necessary for the reduction of polyprenol to dolichol, the lipid anchor for N-glycosylation in the endoplasmic reticulum. Dolichol synthesis is an essential metabolic step in protein glycosylation. The current defect leads to a severely abnormal glycosylation state already in the early phase of the N-glycan biosynthesis pathway in the endoplasmic reticulum. We detected high expression of SRD5A3 in foetal brain tissue, especially in the cerebellum, consistent with the finding of the congenital cerebellar malformations. Based on the overlapping clinical, biochemical and genetic data in this large group of patients with congenital disorders of glycosylation, we define a novel syndrome of cerebellar ataxia associated with congenital eye malformations due to a defect in dolichol metabolism.