De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms.

Determining pathogenicity of genomic variation identified by next-generation sequencing techniques can be supported by recurrent disruptive variants in the same gene in phenotypically similar individuals. However, interpretation of novel variants in a specific gene in individuals with mild-moderate intellectual disability (ID) without recognizable syndromic features can be challenging and reverse phenotyping is often required. We describe 24 individuals with a de novo disease-causing variant in, or partial deletion of, the F-box only protein 11 gene (FBXO11, also known as VIT1 and PRMT9).

-Related Cardiac Disease: Late Onset With a Variable and Mild Phenotype in a Large Cohort of Patients With the Lamin A/C p.(Arg331Gln) Founder Mutation.

Background: Interpretation of missense variants can be especially difficult when the variant is also found in control populations. This is what we encountered for the c.992G>A (p.

Delayed onset of ambulation in boys with Duchenne muscular dystrophy: Potential use as an endpoint in clinical trials.

Individuals with Duchenne muscular dystrophy (DMD) often exhibit delayed motor and cognitive development, including delayed onset of ambulation. Data on age when loss of independent ambulation occurs are well established for DMD; however, age at onset of walking has not been well described. We hypothesize that an effective medication given in early infancy would advance the age when walking is achieved so that it is closer to age-matched norms, and that this discrete event could serve as the primary outcome measure in a clinical trial.

Truncating de novo mutations in the Krüppel-type zinc-finger gene ZNF148 in patients with corpus callosum defects, developmental delay, short stature, and dysmorphisms.

Background: Krüppel-type zinc finger genes (ZNF) constitute a large yet relatively poorly characterized gene family. ZNF genes encode proteins that recognize specific DNA motifs in gene promotors. They act as transcriptional co-activators or -repressors via interaction with chromatin remodeling proteins and other transcription factors.

Epilepsy in KCNH1-related syndromes.

KCNH1 mutations have been identified in patients with Zimmermann-Laband syndrome and Temple-Baraitser syndrome, as well as patients with uncharacterized syndromes with intellectual disability and overlapping features. These syndromes include dysmorphic facial features, nail hypo/aplasia, thumb and skeletal anomalies, intellectual disability, and seizures. We report the epilepsy phenotype in patients with KCNH1 mutations.

Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome.

Mutations in components of the major spliceosome have been described in disorders with craniofacial anomalies, e.g., Nager syndrome and mandibulofacial dysostosis type Guion-Almeida.

Central 22q11.2 deletions.

22q11.2 deletion syndrome is one of the most common microdeletion syndromes. Most patients have a deletion resulting from a recombination of low copy repeat blocks LCR22-A and LCR22-D.

Birth prevalence for congenital limb defects in the northern Netherlands: a 30-year population-based study.

Background: Reported birth prevalences of congenital limb defects (CLD) vary between countries: from 13/10,000 in Finland for the period 1964-1977 to 30.4/10,000 births in Scotland from 1964-1968. Epidemiological studies permit the timely detection of trends in CLD and of associations with other birth defects.

Periconceptional folic acid associated with an increased risk of oral clefts relative to non-folate related malformations in the Northern Netherlands: a population based case-control study.

Periconceptional folic acid has been associated with a reduced risk of neural tube defects, but findings on its effect in oral clefts are largely inconclusive. This case-control study assesses the effects of periconceptional folic acid on cleft risk, using complementary data from the Dutch Oral Cleft Registry and a population-based birth defects registry (Eurocat) of children and foetuses born in the Northern Netherlands between 1997 and 2009. Cases were live-born infants with non-syndromic clefts (n = 367) and controls were infants or foetuses with chromosomal/syndromal (n = 924) or non-folate related anomalies (n = 2,021).

Mutations in MED12 cause X-linked Ohdo syndrome.

Ohdo syndrome comprises a heterogeneous group of disorders characterized by intellectual disability (ID) and typical facial features, including blepharophimosis. Clinically, these blepharophimosis-ID syndromes have been classified in five distinct subgroups, including the Maat-Kievit-Brunner (MKB) type, which, in contrast to the others, is characterized by X-linked inheritance and facial coarsening at older age. We performed exome sequencing in two families, each with two affected males with Ohdo syndrome MKB type.

Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility.

Perlman syndrome is a congenital overgrowth syndrome inherited in an autosomal recessive manner that is associated with Wilms tumor susceptibility. We mapped a previously unknown susceptibility locus to 2q37.1 and identified germline mutations in DIS3L2, a homolog of the Schizosaccharomyces pombe dis3 gene, in individuals with Perlman syndrome.

MYT1L is a candidate gene for intellectual disability in patients with 2p25.3 (2pter) deletions.

A partial deletion of chromosome band 2p25.3 (2pter) is a rarely described cytogenetic aberration in patients with intellectual disability (ID). Using microarrays we identified deletions of 2p25.

Practical guidelines for interpreting copy number gains detected by high-resolution array in routine diagnostics.

The correct interpretation of copy number gains in patients with developmental delay and multiple congenital anomalies is hampered by the large number of copy number variations (CNVs) encountered in healthy individuals. The variable phenotype associated with copy number gains makes interpretation even more difficult. Literature shows that inheritence, size and presence in healthy individuals are commonly used to decide whether a certain copy number gain is pathogenic, but no general consensus has been established.

The international dystrophic epidermolysis bullosa patient registry: an online database of dystrophic epidermolysis bullosa patients and their COL7A1 mutations.

Dystrophic epidermolysis bullosa (DEB) is a heritable blistering disorder that can be inherited autosomal dominantly (DDEB) or recessively (RDEB) and covers a group of several distinctive phenotypes. A large number of unique COL7A1 mutations have been shown to underlie DEB. Although general genotype-phenotype correlation rules have emerged, many exceptions to these rules exist, compromising disease diagnosing and genetic counseling.

The inversa type of recessive dystrophic epidermolysis bullosa is caused by specific arginine and glycine substitutions in type VII collagen.

Background: The inversa type of recessive dystrophic epidermolysis bullosa (RDEB-I) is a rare variant of dystrophic epidermolysis bullosa, characterised by blistering in the body flexures, trunk, and mucosa. The cause of this specific distribution is unknown. So far, 20 COL7A1 genotypes have been described in RDEB-I and genotype-phenotype correlations have not been studied extensively.

The unfolding clinical spectrum of holoprosencephaly due to mutations in SHH, ZIC2, SIX3 and TGIF genes.

Holoprosencephaly is a severe malformation of the brain characterized by abnormal formation and separation of the developing central nervous system. The prevalence is 1:250 during early embryogenesis, the live-born prevalence is 1:16 000. The etiology of HPE is extremely heterogeneous and can be teratogenic or genetic.

Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP.

Wnt signaling is a crucial component of the cell machinery orchestrating a series of physiological processes such as cell survival, proliferation, and migration. Among the plethora of roles that Wnt signaling plays, its canonical branch regulates eye organogenesis and angiogenesis. Mutations in the genes encoding the low density lipoprotein receptor protein 5 (LRP5) and frizzled 4 (FZD4), acting as coreceptors for Wnt ligands, cause familial exudative vitreoretinopathy (FEVR).

Holoprosencephaly and agnathia spectrum: Presentation of two new patients and review of the literature.

Holoprosencephaly (HPE), the most common developmental disorder of the human forebrain, is occasionally associated with the spectrum of agnathia, or virtual absence of the mandible. This condition results in a constellation of structural cerebral and craniofacial abnormalities. Here we present two new patients and review 30 patients from the literature with HPE and variants of agnathia.

Holoprosencephaly and ectrodactyly: Report of three new patients and review of the literature.

Holoprosencephaly (HPE) and ectrodactyly represent congenital malformations of the developing forebrain and developing digits, respectively. The combination of these conditions is rare, with only 15 cases known to date (12 previously reported, and 3 new cases described here). While the findings in these patients overlap with previously described genetic conditions, the similarity in phenotypes among these patients has led to the establishment of a at least one distinct syndrome: HPE, ectrodactyly, and bilateral cleft lip-palate syndrome (OMIM 300571).

Long-term follow-up of patients with recessive dystrophic epidermolysis bullosa in the Netherlands: expansion of the mutation database and unusual phenotype-genotype correlations.

Background: The current classification of recessive dystrophic epidermolysis bullosa (RDEB) comprises two major subtypes: 'severe generalized RDEB' (RDEB-sev gen) with early-onset, extensive, generalized blistering and scarring, complete absence of type VII collagen, and bi-allelic COL7A1 null mutations; milder 'generalized other RDEB' (RDEB-O) with reduced-to-normal type VII collagen expression, and non-null genotypes.

Objective: To search for previously unrecognized phenotype-genotype correlations in 33 Dutch RDEB families.

Methods: We analyzed extensive clinical follow-up data, available for all patients up to 19 years, detailed type VII collagen immunostaining and genotypes, and correlated clinical phenotype to molecular phenotype and genotype.

Ectrodactyly with fibular aplasia: a separate entity?

E/FA is the combination of ectrodactyly (split hand/foot malformation, SHFM) and fibular aplasia. It is a rare disorder considered to be inherited in an autosomal dominant fashion with reduced penetrance and variable expression. In order to determine recurrence risks for the two patients we describe, the literature on inheritance of E/FA was carefully reviewed.

Question mark ears and post-auricular tags.

Questions mark ears are an easily recognisable but uncommon malformation of the external ear. They can be found as an isolated malformation and are a pathognomonic sign of the auriculo-condylar syndrome. An additional unique sign in this syndrome may be present in the form of post-auricular tags.