Mutation of IGFBP7 causes upregulation of BRAF/MEK/ERK pathway and familial retinal arterial macroaneurysms.

Insulin-like growth factor binding proteins (IGFBPs) play important physiological functions through the modulation of IGF signaling as well as IGF-independent mechanisms. Despite the established role of IGFs in development, a similar role for the seven known IGFBPs has not been established in humans. Here, we show that an autosomal-recessive syndrome that consists of progressive retinal arterial macroaneurysms and supravalvular pulmonic stenosis is caused by mutation of IGFBP7.

Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome.

Adams-Oliver syndrome (AOS) is defined by the combination of aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD). It is usually inherited as an autosomal-dominant trait, but autosomal-recessive inheritance has also been documented. In an individual with autosomal-recessive AOS, we combined autozygome analysis with exome sequencing to identify a homozygous truncating mutation in dedicator of cytokinesis 6 gene (DOCK6) which encodes an atypical guanidine exchange factor (GEF) known to activate two members of the Rho GTPase family: Cdc42 and Rac1.

A nullimorphic ERLIN2 mutation defines a complicated hereditary spastic paraplegia locus (SPG18).

Hereditary Spastic Paraplegia (HSP) is a clinically and genetically heterogeneous group of neurological disorders that are characterized by progressive spasticity of the lower extremities. We describe an extended consanguineous Saudi family in which HSP is linked to SPG18, a previously reported autosomal recessive locus, and show that it is associated with a nullimorphic deletion of ERLIN2, a component of endoplasmic reticulum associated degradation. This finding adds to the growing diversity of cellular functions that are now known to be involved in the maintenance of the corticospinal tract neurons.

Deficiency of the cytoskeletal protein SPECC1L leads to oblique facial clefting.

Genetic mutations responsible for oblique facial clefts (ObFC), a unique class of facial malformations, are largely unknown. We show that loss-of-function mutations in SPECC1L are pathogenic for this human developmental disorder and that SPECC1L is a critical organizer of vertebrate facial morphogenesis. During murine embryogenesis, Specc1l is expressed in cell populations of the developing facial primordial, which proliferate and fuse to form the face.

Familial juvenile glaucoma with underlying homozygous p.G61E CYP1B1 mutations.

We describe siblings with familial primary juvenile glaucoma from a consanguineous Saudi Arabian family. The phenotype segregated with homozygous p.G61E CYP1B1 mutations while MYOC mutation was not detected, illustrating that mutations in CYP1B1 rather than mutation in MYOC can underlie familial primary juvenile glaucoma in certain populations.

Mutations in FKBP10 cause both Bruck syndrome and isolated osteogenesis imperfecta in humans.

Bruck syndrome (BS) is an autosomal recessive syndromic form of osteogenesis imperfecta (OI) that is characterized by the additional presence of pterygium formation. We have recently shown that FKBP10 previously reported as a novel autosomal recessive OI gene also defines a novel Bruck syndrome locus (BKS3). In this manuscript, we extend our analysis to describe a mutation previously described in isolated OI patients and show that it results in BS phenotype in a Saudi family.

Ritscher-Schinzel (cranio-cerebello-cardiac, 3C) syndrome: report of four new cases with renal involvement.

Ritscher-Schinzel (cranio-cerebello-cardiac, 3C) syndrome is a multiple congenital anomaly syndrome that is considered to be autosomal recessive although no genetic defect has yet been identified. In a consanguineous Saudi family, we have identified four patients who meet the diagnostic criteria of 3C syndrome and who also have alopecia, camptodactaly and significant renal involvement. Interestingly, two otherwise normal female siblings have unilateral renal agenesis only.

GM2 gangliosidosis in Saudi Arabia: multiple mutations and considerations for future carrier screening.

The GM2 gangliosidose, Tay-Sachs and Sandhoff diseases, are a class of lysosomal storage diseases in which relentless neurodegeneration results in devastating neurological disability and premature death. Primary prevention is the most effective intervention since no effective therapy is currently available. An extremely successful model for the prevention of GM2 gangliosidosis in the Ashkenazi Jewish community is largely attributable to the very limited number of founder mutations in that population.

Human mutations in NDE1 cause extreme microcephaly with lissencephaly [corrected].

Genes disrupted in human microcephaly (meaning "small brain") define key regulators of neural progenitor proliferation and cell-fate specification. In comparison, genes mutated in human lissencephaly (lissos means smooth and cephalos means brain) highlight critical regulators of neuronal migration. Here, we report two families with extreme microcephaly and grossly simplified cortical gyral structure, a condition referred to as microlissencephaly, and show that they carry homozygous frameshift mutations in NDE1, which encodes a multidomain protein that localizes to the centrosome and mitotic spindle poles.

A TCTN2 mutation defines a novel Meckel Gruber syndrome locus.

Meckel Gruber syndrome (MKS) is an autosomal recessive multisystem disorder that represents a severe form of ciliopathy in humans and is characterized by significant genetic heterogeneity. In this article, we describe the identification of a novel MKS locus MKS8 that we map to TCTN2, in a multiplex consanguineous family. TCTN2 is a paralog of the recently identified Tectonic 1, which has been shown to modulate sonic hedgehog signaling.

Mutations in the RNA granule component TDRD7 cause cataract and glaucoma.

The precise transcriptional regulation of gene expression is essential for vertebrate development, but the role of posttranscriptional regulatory mechanisms is less clear. Cytoplasmic RNA granules (RGs) function in the posttranscriptional control of gene expression, but the extent of RG involvement in organogenesis is unknown. We describe two human cases of pediatric cataract with loss-of-function mutations in TDRD7 and demonstrate that Tdrd7 nullizygosity in mouse causes cataracts, as well as glaucoma and an arrest in spermatogenesis.

Genetic and genomic analysis of classic aniridia in Saudi Arabia.

Purpose: To determine the genetic and genomic alterations underlying classic aniridia in Saudi Arabia, a region with social preference for consanguineous marriage.

Methods: Prospective study of consecutive patients referred to a pediatric ophthalmologist in Saudi Arabia (2005-2009). All patients had paired box gene 6 (PAX6) analysis (sequencing and multiplex ligation-dependent probe amplification analysis if sequencing was normal).

Molecular characterization of newborn glaucoma including a distinct aniridic phenotype.

Purpose: To characterize the underlying genetic defect in otherwise healthy Saudi newborns with buphthalmos, including those with iris abnormalities.

Methods: Prospective case series of affected Saudi Arabian probands who were referred for genetic counseling over a 4 year period. All had CYP1B1 sequencing.

Functional analysis of BBS3 A89V that results in non-syndromic retinal degeneration.

Bardet-Biedl syndrome (BBS) is a syndromic form of retinal degeneration. Recently, homozygosity mapping with a consanguineous family with isolated retinitis pigmentosa identified a missense mutation in BBS3, a known BBS gene. The mutation in BBS3 encodes a single amino acid change at position 89 from alanine to valine.

Arthrogryposis, perthes disease, and upward gaze palsy: a novel autosomal recessive syndromic form of arthrogryposis.

In this article, the unusual combination of arthrogryposis, upward gaze palsy, and Perthes disease in two sisters and their cousin who are all part of an extended consanguineous Saudi family is reported. All patients had difficult to control bronchial asthma and subtle facial dysmorphism. Two of the three had pyloric stenosis, two were intellectually normal, and one had academic problems but had a history of birth hypoxia.

Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.

3MC syndrome has been proposed as a unifying term encompassing the overlapping Carnevale, Mingarelli, Malpuech and Michels syndromes. These rare autosomal recessive disorders exhibit a spectrum of developmental features, including characteristic facial dysmorphism, cleft lip and/or palate, craniosynostosis, learning disability and genital, limb and vesicorenal anomalies. Here we studied 11 families with 3MC syndrome and identified two mutated genes, COLEC11 and MASP1, both of which encode proteins in the lectin complement pathway (collectin kidney 1 (CL-K1) and MASP-1 and MASP-3, respectively).

Autozygome decoded.

Consanguineous unions permit the "reunion" of ancestral chromosomal segments in a pattern referred to as "autozygosity," which is essentially a special form of homozygosity. This has long been exploited as a gene mapping tool because it is relatively easy to track a recessive mutation by the surrounding pattern of homozygous markers. The recent advent of single nucleotide polymorphism microarrays has rapidly replaced the historical use of microsatellites for this purpose.

Identification of differentially expressed proteins in the aqueous humor of primary congenital glaucoma.

Primary Congenital Glaucoma (PCG) is an autosomal recessive disease caused by an abnormal development of the anterior chamber angle. Although, PCG has been linked to several genetic loci, the role that the genes at these loci or their encoded proteins play in the pathophysiology of PCG and development of the anterior chamber is not known. To identify proteins that may be altered in PCG and that may help in understanding the underlying pathophysiology of the disease, we took a global proteomics approach.

Study of consanguineous populations can improve the annotation of SNP databases.

Our view of SNPs has evolved significantly from harmless mutational events that accumulated through the history of human race to important players in human health and disease. As a result, determining the pathologic vs. benign nature of SNPs on pure statistical basis is now viewed as too simplistic.

Mental retardation, growth retardation, unusual nose, and open mouth: an autosomal recessive entity.

In this paper, I describe the investigations in three members of an extended consanguineous family from Saudi Arabia, in which nine members show severe mental retardation, long eyelashes, high nasal bridge, underdeveloped malae, low hanging columella, thin upper vermillion, and everted lower vermillion, retrognathia, and an open mouth apparently caused by mandibular dentoalveolar protrusion. Pedigree analysis makes it likely that this is an autosomal recessively inherited disorder. A detailed literature search failed to show a similar entity.