Nuclear envelopathies comprise a heterogeneous group of diseases caused by mutations in genes encoding nuclear envelope proteins. Mutations affecting lamina-associated polypeptide 1 (LAP1) result in two discrete phenotypes of muscular dystrophy and progressive dystonia with cerebellar atrophy. We report 7 patients presenting at birth with severe progressive neurological impairment, bilateral cataract, growth retardation and early lethality. All the patients are homozygous for a nonsense mutation in the TOR1AIP1 gene resulting in the loss of both protein isoforms LAP1B and LAP1C. Patient-derived fibroblasts exhibit changes in nuclear envelope morphology and large nuclear-spanning channels containing trapped cytoplasmic organelles. Decreased and inefficient cellular motility is also observed in these fibroblasts. Our study describes the complete absence of both major human LAP1 isoforms, underscoring their crucial role in early development and organogenesis. LAP1-associated defects may thus comprise a broad clinical spectrum depending on the availability of both isoforms in the nuclear envelope throughout life.

Severe congenital neutropenia type 4 (SCN4) is an autosomal recessive condition, which was defined recently with identification of the causative mutations in G6PC3. To date there are only three reports in the literature describing patients with SCN4 with mutations in the G6PC3 gene. We report four individuals with SCN4 who belong to a single large consanguineous kindred. We provide an overview of the non-haematological features of the condition with a focus on the adult phenotype, which has not been previously described in detail. We show that the superficial venous changes seen in SCN4 patients can develop into varicose veins and venous ulcers in adulthood. We review the range of congenital anomalies associated with SCN4. We demonstrate that secundum atrial septal defect, patent ductus arteriosus and valvular defects are the most frequent cardiac anomalies in SCN4. Drawing parallels with type 1 glycogen storage disease, we propose that poor growth of prenatal onset, mild-to-moderate learning disability, primary pulmonary hypertension, delayed or incomplete puberty, hypothyroidism and dysmorphism likely represent features of this syndrome. We also suggest monitoring for lipid anomalies, and kidney and liver function in affected patients. Delineation of the SCN4 phenotype may help in appropriate treatment and management and provide further insights into the pathogenesis of this multisystem disease.

Primary Ovarian Insufficiency (POI) affects ~1% of women under forty. Exome sequencing of two Finnish sisters with non-syndromic POI revealed a homozygous mutation in FANCM, leading to a truncated protein (p.Gln1701*). FANCM is a DNA-damage response gene whose heterozygous mutations predispose to breast cancer. Compared to the mother's cells, the patients' lymphocytes displayed higher levels of basal and mitomycin C (MMC)-induced chromosomal abnormalities. Their lymphoblasts were hypersensitive to MMC and MMC-induced monoubiquitination of FANCD2 was impaired. Genetic complementation of patient's cells with wild-type FANCM improved their resistance to MMC re-establishing FANCD2 monoubiquitination. FANCM was more strongly expressed in human fetal germ cells than in somatic cells. FANCM protein was preferentially expressed along the chromosomes in pachytene cells, which undergo meiotic recombination. This mutation may provoke meiotic defects leading to a depleted follicular stock, as in Fancm-/-mice. Our findings document the first Mendelian phenotype due to a biallelic FANCM mutation.

The 3MC syndromes are a group of rare autosomal recessive disorders where the main clinical features are cleft lip and palate, hypertelorism, highly arched eyebrows, caudal appendage, postnatal growth deficiency, and genitourinary tract anomalies. Ophthalmological abnormalities, most notably anterior chamber defects may also be seen. We describe the clinical and molecular findings in 13 individuals with suspected 3MC syndrome from 12 previously unreported families. The exclusion of the MASP1 and COLEC11 Loci in two individuals from different consanguineous families and the absence of mutations in four further individuals sequenced for both genes raises the possibility that that there is further genetic heterogeneity of 3MC syndrome.