Clinical variability in DYNC2H1-related skeletal ciliopathies includes Ellis-van Creveld syndrome.

Deleterious variants of DYNC2H1 gene are associated with a wide spectrum of skeletal ciliopathies (SC). We used targeted parallel sequencing to analyze 25 molecularly unsolved families with different SCs. Deleterious DYNC2H1 variants were found in six sporadic patients and two monozygotic (MZ) twins. Clinical diagnoses included short rib-polydactyly type 3 in two cases, and asphyxiating thoracic dystrophy (ATD) in one case. Remarkably, clinical diagnosis fitted with EvC, mixed ATD/EvC and short rib-polydactyly/EvC phenotypes in three sporadic patients and the MZ twins. EvC/EvC-like features always occurred in compound heterozygotes sharing a previously unreported splice site change (c.6140-5A>G) or compound heterozygotes for two missense variants. These results expand the DYNC2H1 mutational repertoire and its clinical spectrum, suggesting that EvC may be occasionally caused by DYNC2H1 variants presumably acting as hypomorphic alleles.

Germline variants in genes of the subcortical maternal complex and Multilocus Imprinting Disturbance are associated with miscarriage/infertility or Beckwith-Wiedemann progeny.

Beckwith-Wiedemann syndrome (BWS, OMIM # 130650) is an imprinting disorder, associated with overgrowth and increased risk of embryonal tumors. Patients carrying hypomethylation in the KCNQ1OT1:TSS DMR (11p15.5) show MLID (Multilocus Imprinting Disturbance) upon epimutations at other imprinted regions. Few cases of BWS MLID's mothers with biallelic pathogenetic variants in maternal effect genes, mainly components of the subcortical maternal complex, are reported. We describe two families, one with a history of conception difficulties with a novel homozygous nonsense NLRP2 variant and another experiencing 8 miscarriages with a compound heterozygous PADI6 variant.

Recurrent NF1 gene variants and their genotype/phenotype correlations in patients with Neurofibromatosis type I.

Neurofibromatosis type I, a genetic condition due to pathogenic variants in the NF1 gene, is burdened by a high rate of complications, including neoplasms, which increase morbidity and mortality for the disease. We retrospectively re-evaluated the NF1 gene variants found in the period 2000-2019 and we studied for genotype/phenotype correlations of disease complications and neoplasms 34 variants, which were shared by at least two unrelated families (range 2-11) for a total 141 of probands and 21 relatives affected by Neurofibromatosis type I. Recurrent variants could be ascribed to the most common mutational mechanisms (C to T transition, microsatellite slippage, non-homologous recombination). In genotype/phenotype correlations, the variants p.Arg440*, p.Tyr489Cys, and p.Arg1947*, together with the gross gene deletions, displayed the highest rates of complications. When considering neoplasms, carriers of variants falling in the extradomain region at the 5' end of NF1 had a lower age-related cancer frequency than the rest of the gene sequence, showing a borderline significance (p = 0.045), which was not conserved after correction with covariates. We conclude that (1) hotspots in NF1 occur via different mutational mechanisms, (2) several variants are associated with high rates of complications and cancers, and (3) there is an initial evidence toward a lower cancer risk for carriers of variants in the 5' end of the NF1 gene although not significant at the multivariate analysis.

Hypoglycemia due to PI3K/AKT/mTOR signaling pathway defects: two novel cases and review of the literature.

INTRODUCTION: The PI3K/AKT/mTOR signaling pathway is important for the regulation of multiple biological processes, including cellular growth and glucose metabolism. Defects of the PI3K/AKT/mTOR signaling pathway are not usually considered among the genetic causes of recurrent hypoglycemia in childhood. However, accumulating evidence links hypoglycemia with defects of this pathway. CASE REPORTS AND REVIEW: We describe here two cases of macrocephaly and hypoglycemia bearing genetic defects in genes involved in the PI3K/AKT/mTOR pathway. The first patient was diagnosed with a PTEN hamartoma tumour syndrome (PTHS) due to the de novo germline missense mutation c.[492 + 1G > A] of the PTEN gene. The second patient presented the autosomal dominant mental retardation-35 (MDR35) due to the heterozygous missense mutation c.592G > A in the PPP2R5D gene. A review of the literature on hypoglycemia and PI3K/AKT/mTOR signaling pathway defects, with a special focus on the metabolic characterization of hypoglycemia, is included. CONCLUSIONS: PI3K/AKT/mTOR pathway defects should be included in the differential diagnosis of patients with hypoglycemia and macrocephaly. Clinical suspicion and molecular confirmation are important, not just for an accurate genetic counselling but also for defining the follow-up management, including cancer surveillance. The biochemical profile of hypoglycemia varies among patients. While most patients are characterized by low plasmatic insulin levels, hyperinsulinemia has also been observed. Large patient cohorts are needed to gain a comprehensive profile of the biochemical patterns of hypoglycemia in such defects and eventually guide targeted therapeutic interventions.

Terminal osseous dysplasia with pigmentary defects: clinical description of a new family.

Terminal osseous dysplasia with pigmentary defects is an extremely rare condition characterized by the triad of pigmentary anomalies of the skin, skeletal abnormalities of the limbs and recurring digital fibromatosis of childhood, with considerable interfamilial and intrafamilial variability of expression. It has recently been added to the small group of X-linked dominant disorder with prenatal male lethality on the basis of a four-generation pedigree in which only females were affected, male progeny was decreased and the number of spontaneous abortions was increased. In this clinical report, we describe a 2-year-old girl with full expression of the syndrome including skin defects, skeletal anomalies and recurrent fibromatosis of fingers and toes and her mother who presents with only multiple hypertrophic oral frenula. As previously demonstrated, our patients also show an extremely skewed X-inactivation on blood cells, strongly suggesting that there is selective disadvantage for cells carrying the mutated gene on their active X chromosome. Terminal osseous dysplasia with pigmentary defects could represent an additional example of extreme intrafamilial variability as already described for other X-linked dominant disorders.