SOX5: Lamb-Shaffer syndrome-A case series further expanding the phenotypic spectrum.

To delineate further the clinical phenotype of Lamb-Shaffer Syndrome (LSS) 16 unpublished patients with heterozygous variation in SOX5 were identified either through the UK Decipher database or the study team was contacted by clinicians directly. Clinical phenotyping tables were completed for each patient by their responsible clinical geneticist. Photos and clinical features were compared to assess key phenotypes and genotype-phenotype correlation.

Traboulsi syndrome caused by mutations in ASPH: An autosomal recessive disorder with overlapping features of Marfan syndrome.

Traboulsi syndrome, otherwise known as facial dysmorphism, lens dislocation, anterior-segment abnormalities and spontaneous filtering blebs, is an autosomal recessive condition associated with characteristic ocular features including dislocated crystalline lenses, anterior segment abnormalities and in some individuals, non-traumatic conjunctival cysts. There is a distinctive facial appearance which includes flattened malar region with convex nasal ridge. Alterations in the aspartate beta-hydroxylase (ASPH) gene are known to be the cause of the condition.

Heterozygous variants in ZBTB7A cause a neurodevelopmental disorder associated with symptomatic overgrowth of pharyngeal lymphoid tissue, macrocephaly, and elevated fetal hemoglobin.

By clinical whole exome sequencing, we identified 12 individuals with ages 3 to 37 years, including three individuals from the same family, with a consistent phenotype of intellectual disability (ID), macrocephaly, and overgrowth of adenoid tissue. All 12 individuals harbored a rare heterozygous variant in ZBTB7A which encodes the transcription factor Zinc finger and BTB-domain containing protein 7A, known to play a role in lympho- and hematopoiesis. ID was generally mild.

Genotype-phenotype correlation at codon 1740 of SETD2.

The SET domain containing 2, histone lysine methyltransferase encoded by SETD2 is a dual-function methyltransferase for histones and microtubules and plays an important role for transcriptional regulation, genomic stability, and cytoskeletal functions. Specifically, SETD2 is associated with trimethylation of histone H3 at lysine 36 (H3K36me3) and methylation of α-tubulin at lysine 40. Heterozygous loss of function and missense variants have previously been described with Luscan-Lumish syndrome (LLS), which is characterized by overgrowth, neurodevelopmental features, and absence of overt congenital anomalies.

A novel lethal recognizable polymicrogyric syndrome caused by ATP1A2 homozygous truncating variants.

Polymicrogyria is a heterogeneous malformation of cortical development microscopically defined by an excessive folding of the cortical mantle resulting in small gyri with a fused surface. Polymicrogyria is responsible for a wide range of neurological symptoms (e.g.

De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.

The Mediator is an evolutionarily conserved, multi-subunit complex that regulates multiple steps of transcription. Mediator activity is regulated by the reversible association of a four-subunit module comprising CDK8 or CDK19 kinases, together with cyclin C, MED12 or MED12L, and MED13 or MED13L. Mutations in MED12, MED13, and MED13L were previously identified in syndromic developmental disorders with overlapping phenotypes.

Interstitial microdeletion of 17q11.2 is associated with hypotonia, fatigue, intellectual disability, and a subtle facial phenotype in three unrelated patients.

Over the past decade chromosomal microarray analysis (array CGH) has allowed the discovery of many novel disease-causing recurrent microdeletion and microduplication syndromes. Here we present three unrelated patients (2F; 1M) from three different countries, with developmental delay, intellectual disability, hypotonia, fatigue, and highly similar dysmorphic facial features. Shared facial features are a broad and wide forehead, similar shape of the eyes with long palpebral fissures, a bulbous tip of the nose and thick lips.

Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families.

Discovery of most autosomal recessive disease-associated genes has involved analysis of large, often consanguineous multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of new dominant causes of rare, genetically heterogeneous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios. Here we analyzed 4,125 families with diverse, rare and genetically heterogeneous developmental disorders and identified four new autosomal recessive disorders.

Improved final height with long-term growth hormone treatment in Noonan syndrome.

Aim: To assess whether children with Noonan syndrome on long-term growth hormone (GH) therapy improve their final height to near mid-parental height.

Methods: Twenty-five prepubertal children (13 girls) with Noonan syndrome (NS) were studied. A single clinician made the diagnosis based on clinical criteria.