Elsahy–Waters syndrome is caused by biallelic mutations in CDH11

Elsahy–Waters syndrome (EWS), also known as branchial–skeletal–genital syndrome, is a distinct dysmorphology syndrome characterized by facial asymmetry, broad forehead, marked hypertelorism with proptosis, short and broad nose, midface hypoplasia, intellectual disability, and hypospadias. We have recently published a homozygous potential loss of function variant in CDH11 in a boy with a striking resemblance to EWS. More recently, another homozygous truncating variant in CDH11 was reported in two siblings with suspected EWS. Here, we describe in detail the clinical phenotype of the original CDH11‐related patient with EWS as well as a previously unreported EWS‐affected girl who was also found to have a novel homozygous truncating variant in CDH11, which confirms that EWS is caused by biallelic CDH11 loss of function mutations. Clinical features in the four CDH11 mutation‐positive individuals confirm the established core phenotype of EWS. Additionally, we identify upper eyelid coloboma as a new, though infrequent clinical feature. The pathomechanism underlying EWS remains unclear, although the limited phenotypic data on the Cdh11^?/? mouse suggest that this is a potentially helpful model to explore the craniofacial and brain development in EWS‐affected individuals.

     

Genomic analysis of primordial dwarfism reveals novel disease genes

Primordial dwarfism (PD) is a disease in which severely impaired fetal growth persists throughout postnatal development and results in stunted adult size. The condition is highly heterogeneous clinically, but the use of certain phenotypic aspects such as head circumference and facial appearance has proven helpful in defining clinical subgroups. In this study, we present the results of clinical and genomic characterization of 16 new patients in whom a broad definition of PD was used (e.g., 3M syndrome was included). We report a novel PD syndrome with distinct facies in two unrelated patients, each with a different homozygous truncating mutation in CRIPT. Our analysis also reveals, in addition to mutations in known PD disease genes, the first instance of biallelic truncating BRCA2 mutation causing PD with normal bone marrow analysis. In addition, we have identified a novel locus for Seckel syndrome based on a consanguineous multiplex family and identified a homozygous truncating mutation in DNA2 as the likely cause. An additional novel PD disease candidate gene XRCC4 was identified by autozygome/exome analysis, and the knockout mouse phenotype is highly compatible with PD. Thus, we add a number of novel genes to the growing list of PD-linked genes, including one which we show to be linked to a novel PD syndrome with a distinct facial appearance. PD is extremely heterogeneous genetically and clinically, and genomic tools are often required to reach a molecular diagnosis.Growth is a fundamental trait of living organisms that is achieved primarily through a positive balance between cellular proliferation and apoptosis. In humans, disorders of growth are common reasons for referral to pediatric endocrinology because the hormonal axis plays a critical role in controlling growth (Daniel et al. 2008). However, many syndromes are known to cause severely stunted growth despite a normal hormonal axis, the most notable of which are skeletal dysplasias, although these represent a selective defect in bony growth. On the other hand, generalized growth deficiency states that are nonhormonal in etiology and are not related to a negative caloric balance offer a unique opportunity to explore factors that control organismal growth at a more fundamental level and are likely to contribute to the ∼90% of failure-to-thrive children in whom no specific etiology is identified (Jaffe 2011). Severe failure to thrive is commonly associated with a wide array of chromosomal aberrations, which attests to a role played by the genes in growth control, but assigning such a role to individual genes is not usually possible due to the nature of these chromosomal aberrations. On the other hand, single gene mutations that are associated with growth deficiency lend themselves readily to gene mapping strategies that have gained more speed and efficiency recently with the advent of next-generation sequencing.Primordial dwarfism (PD) refers to severely stunted growth that has its onset prenatally. The condition is highly heterogeneous clinically, but the use of certain phenotypic aspects can help define clinical subgroups. For example, a distinct facial profile and associated microcephaly defines Seckel syndrome (Seckel 1960; Majewski and Goecke 1982). Other PD syndromes can also be readily recognized by their characteristic facial appearance, such as 3M syndrome and POC1A-related PD, both of which lack microcephaly as a diagnostic feature (Al-Dosari et al. 2012; Shaheen et al. 2012). This clinical classification allowed more homogeneous patient populations to be grouped together, which facilitated disease gene identification, especially in the last few years. The identification of these disease genes has unraveled novel pathways that control growth (Klingseisen and Jackson 2011). These pathways include (1) abnormal mitosis (CENPJ- and PCNT-related Seckel syndrome and microcephalic osteodysplastic primordial dwarfism) (Griffith et al. 2007; Al-Dosari et al. 2010), (2) abnormal IGF2 expression (Russel-Silver syndrome) (Netchine et al. 2007), (3) perturbed DNA damage response (ATR-, ATRIP- and RBBP8-related Seckel syndrome) (O''Driscoll et al. 2003; Qvist et al. 2011; Ogi et al. 2012), (4) defective spliceosomal machinery (RNU4ATAC [formerly referred to as U4atac]-related microcephalic osteodysplastic primordial dwarfism) (He et al. 2011), and (5) abnormal replication licensing (in Meier-Gorlin syndrome) (Bicknell et al. 2011; Kuo et al. 2012).Little is known about the contribution of each of the above genes to the mutation burden in PD, although it is widely believed that its genetic heterogeneity is far from being fully captured (Klingseisen and Jackson 2011). Since almost all known PD disease genes are autosomal recessive in nature and since the highly consanguineous nature of the Saudi population is likely to facilitate both the occurrence of these recessive mutations as well as their identification through autozygome analysis (as we have shown for CENPJ-related Seckel syndrome, POC1A-related PD, and 3M syndrome), we conducted a study on PD patients who were referred to the clinical genetics service in order to examine the contribution of known genes and to identify novel genes. This is the largest comprehensive genomic study on PD that we are aware of and it significantly expands the genetic heterogeneity of this disorder, as we show below.     

Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities

Temtamy syndrome is a syndromic form of intellectual disability characterized by ocular involvement, epilepsy and dysgenesis of the corpus callosum. After we initially mapped the disease to C12orf57, we noted a high carrier frequency of an ancient startloss founder mutation [c.1A>G; p.M1?] in our population, and variable phenotypic expressivity in newly identified cases. This study aims to combine 33 previously published patients with 23 who are described here for the first time to further delineate the phenotype of this syndrome. In addition to the known p.M1? founder, we describe four novel homozygous variants, thus increasing the number of Temtamy syndrome‐related C12orf57 variants to seven, all but one predicted to be loss of function. While all patients presented with intellectual disability/developmental delay, the frequency of other phenotypic features was variable: 73.2% (41/56) had epilepsy, 63% (34/54) had corpus callosal abnormalities, 14.5% (8/55) had coloboma, and 16.4% (9/55) had microphthalmia. Our analysis also revealed a high frequency of less recognized features such as congenital heart disease (51.4%), and brain white matter abnormalities (38%, 19/50). We conclude that C12orf57 variants should be considered in the etiology of developmental delay/intellectual disability, even when typical syndromic features are lacking, especially in those who trace their ancestry to Saudi Arabia where a founder C12orf57 mutation is among the most common recessive causes of intellectual disability.

     

Neuronal ceroid lipofuscinosis caused by MFSD8 mutations: a common theme emerging

Neuronal ceroid lipofuscinoses (NCLs) are a group of lysosomal neurodegenerative disorders that have in common the characteristic accumulation of abnormal storage material. Old clinical classification based on age of onset is now being revisited with the quickly accumulating knowledge of the various genetic defects that underlie this group of genetically heterogeneous disorders. We report our linkage data on a family with late-infantile NCL and show that the disease in this family is due to a homozygous novel mutation in the most recently described NCL gene (MFSD8). We use clinical data from our patients and the few others that have previously been reported to delineate the phenotype associated with mutations in this gene. We conclude that the phenotype is fairly consistent, which is a helpful guide to clinicians as they decide on the most cost-effective molecular testing strategies for NCLs.     

ConsCal: A tool to aid medical genetics professionals in consanguineous populations

Consanguineous populations have a higher frequency of autosomal recessive diseases when compared to the rest of the world. This frequency is high enough that families in these populations may even have multiple autosomal recessive diseases. The recurrence risk calculation for the various combinations becomes increasingly more difficult as more recessive diseases are encountered in a family. Another challenge in these populations is investigating the pathogenicity of a variant by considering its segregation with the phenotype. Consanguinity causes the appearance of many homozygous variants due to the identity by descent phenomenon. As the number of these variants increases, so does the percentage of novel variants that need to be classified using segregation. Furthermore, the complexity of calculating the segregation power increases with the level of inbreeding, and in the case of consanguineous families, their pedigrees tend to be very complex. With the aim of addressing these two challenges using a mathematical algorithm, ConsCal, a tool made to specifically cater to medical genetics professionals working with consanguineous populations, was developed. The user-friendly tool contains two primary functions. It simplifies recurrence risk calculations for any combination of autosomal recessive diseases and analyzes familial segregation data to assign a numerical value to the segregation power of a given variant to aid in its classification. As the use of genomics becomes more widespread, this tool can help address the growing need in calculating recurrence risk and segregation power in consanguineous populations.     

A Novel Homozygous Mutation in G6PC3 Presenting as Cyclic Neutropenia and Severe Congenital Neutropenia in the Same Family

Purpose

Patients with autosomal recessive cyclic neutropenia have no known causative genetic defect yet.

Methods

Autozygosity mapping on two branches of an extended multiplex consanguineous family presenting with cyclic neutropenia or severe congenital neutropenia to look for candidate gene, followed by candidate gene selection and sequencing.

Results

A single autozygous interval on Chr17:33,901,938-45,675,414 that is exclusively shared by the affected members was identified. This interval spans 11.8 Mb and contains 30 genes. Review of these genes highlighted G6PC3 as the most likely candidate given its known role in neutrophil biology. Direct sequencing revealed a novel homozygous mutation (NM_138387.3, c.974T?>?G, p.Leu325Arg). Two of our patients had associated congenital defects that are known to occur in patients with G6PC3 mutations, including congenital heart disease and intermittent thrombocytopenia.

Conclusion

Biallelic G6PC3 defects should be considered in patients with autosomal recessive cyclic neutropenia, especially those with typical associated congenital defects.     

An autosomal recessive syndrome of severe cognitive impairment, dysmorphic facies and skeletal abnormalities maps to the long arm of chromosome 17

Cognitive impairment (CI) is one of the most challenging referrals to the clinical genetics service. The different algorithms proposed to assist in the molecular diagnosis of CI rest largely on the distinction between syndromic and non-syndromic forms. We have identified what appears to be a novel syndromic form of CI, the variable phenotype of which comprises severe CI, hirsutism, dysmorphic facies and skeletal abnormalities, and have mapped it to a single locus on chromosome 17q21.31-17q22 spanning 12.2 Mb. Two candidate genes, HOXB6 and PPP1R9B were sequenced but no pathogenic alterations were identified. This report adds to the growing list of autosomal recessive syndromic CI conditions and defines a linkage interval harboring a gene which probably plays a vital role in brain development.     

Clinical,biochemical and molecular characterization of peroxisomal diseases in Arabs

Shaheen R, Al‐Dirbashi OY, Al‐Hassnan ZN, Al‐Owain M, Makhsheed N, Basheeri F, Seidahmed MZ, Salih MAM, Faqih E, Zaidan H, Al‐Sayed M, Rahbeeni Z, Al‐Sheddi T, Hashem M, Kurdi W, Shimozawa N, Alkuraya FS. Clinical, biochemical and molecular characterization of peroxisomal diseases in Arabs. Peroxisomes are single membrane‐bound cellular organelles that carry out critical metabolic reactions perturbation of which leads to an array of clinical phenotypes known as peroxisomal disorders (PD). In this study, the largest of its kind in the Middle East, we sought to comprehensively characterize these rare disorders at the clinical, biochemical and molecular levels. Over a 2‐year period, we have enrolled 17 patients representing 16 Arab families. Zellweger‐spectrum phenotype was observed in 12 patients and the remaining 5 had the rhizomelic chondrodysplasia punctata phenotype. We show that homozygosity mapping is a cost‐effective strategy that enabled the identification of the underlying genetic defect in 100% of the cases. The pathogenic nature of the mutations identified was confirmed by immunofluorescence and complementation assays. We confirm the genetic heterogeneity of PD in our population, expand the pool of pathogenic alleles and draw some phenotype/genotype correlations.