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Osteogenesis imperfecta (OI) is the most common skeletal dysplasia, which predisposes to recurrent fractures and bone deformity and presents with wide clinical variability. More than 80% of OI cases are related to dominantly inherited mutations in COL1A1 or COL1A2. The rest of the cases, however, involve many other noncollagen genes, all of which are autosomal‐recessively inherited, except for IFITM5 and WNT1, which are also associated with autosomal dominant OI. Since 2012, a single recurrent heterozygous mutation in IFITM5 (c.‐14C>T) has been shown to underlie OI type V. Although this is the most common OI‐causing mutation in IFITM5, a second, less common mutation in IFITM5, c.119C>T (p.Ser40Leu), has been identified, which is not associated with the OI type V phenotype. In this report, we describe the clinical and radiological features of a further patient with this uncommon mutation in IFITM5 (c.119C>T, p.Ser40Leu). The patient presented with prenatal signs of severe OI and developed extreme short stature with short and bowed limbs, relative macrocephaly, scoliosis, vertebral compression, and a hypoplastic thorax. He had global developmental delay, recurrent respiratory problems, and required special family care and multidisciplinary treatment. To date, all patients with the uncommon c.119C>T mutation have presented with severe OI, rather than OI type V. Thus, this report further strengthens the case for a genotype–phenotype correlation for IFITM5‐related OI. [ABSTRACT FROM AUTHOR]

Background Very recently, compound heterozygous loss-of-function mutations in TELO2 were shown to underlie the newly-described You-Hoover-Fong syndrome. TELO2 forms part of the co-chaperone triple T complex ( TTT complex), which plays an important role in the maturation and stabilization of the phosphatidylinositol 3-kinase-related protein kinases ( PIKKs). Patients with mutations in TELO2 present with microcephaly and associated intellectual disability, postnatal growth retardation and dysmorphic features. Here, we describe Danish sisters with two novel mutations in TELO2. In particular, we highlight the clinical features of the 22-year index patient, which are more severe than the original patients described, thereby expanding the clinical spectrum of YHFS. Methods The index patient was clinically examined and subsequently exome sequencing on her DNA was performed using the NimbleGen SeqCap EZ Human Exome Library v2.0 enrichment kit on an Illumina HiSeq2000 sequencer. Results Two novel, compound heterozygous mutations in TELO2 were identified in the index patient and her deceased older sister. Both have clinical features in keeping with the original YHFS patients, although the index patient seems to represent the severe end of the clinical spectrum with very marked prenatal onset growth retardation and microcephaly, severe global developmental delay and facial dysmorphic features. Additional clinical findings include eye anomalies (bilateral congenital cataracts, retinitis pigmentosa, convergent squint), bilateral conductive hearing loss, an abnormal kidney and seizures. Conclusion This report of Danish siblings with YHFS serves to expand the presentation of this new syndrome to include features in keeping with a form of microcephalic primordial dwarfism on the severe end of the clinical spectrum, and adds two novel mutations to the TELO2 mutational spectrum. [ABSTRACT FROM AUTHOR]

Filippi syndrome is a rare, presumably autosomal-recessive disorder characterized by microcephaly, pre- and postnatal growth failure, syndactyly, and distinctive facial features, including a broad nasal bridge and underdeveloped alae nasi. Some affected individuals have intellectual disability, seizures, undescended testicles in males, and teeth and hair abnormalities. We performed homozygosity mapping and whole-exome sequencing in a Sardinian family with two affected children and identified a homozygous frameshift mutation, c.571dupA (p.Ile191Asnfs ∗ 6), in CKAP2L , encoding the protein cytoskeleton-associated protein 2-like (CKAP2L). The function of this protein was unknown until it was rediscovered in mice as Radmis (radial fiber and mitotic spindle) and shown to play a pivotal role in cell division of neural progenitors. Sanger sequencing of CKAP2L in a further eight unrelated individuals with clinical features consistent with Filippi syndrome revealed biallelic mutations in four subjects. In contrast to wild-type lymphoblastoid cell lines (LCLs), dividing LCLs established from the individuals homozygous for the c.571dupA mutation did not show CKAP2L at the spindle poles. Furthermore, in cells from the affected individuals, we observed an increase in the number of disorganized spindle microtubules owing to multipolar configurations and defects in chromosome segregation. The observed cellular phenotypes are in keeping with data from in vitro and in vivo knockdown studies performed in human cells and mice, respectively. Our findings show that loss-of-function mutations in CKAP2L are a major cause of Filippi syndrome. [ABSTRACT FROM AUTHOR]