Noonan syndrome (NS)/Noonan syndrome with multiple lentigines (NSML) is commonly characterized by distinct facial features, a short stature, cardiac problems, and a developmental delay of variable degrees. However, as many as 50% of individuals diagnosed with NS/NSML have a mildly affected parent or relative due to variable expressivity and possibly incomplete penetrance of the disorder, and those who are recognized to have NS only after a diagnosis are established in a more obviously affected index case.
In order to collect intergenerational data reported from previous studies, electronic journal databases containing information on the molecular genetics of PTPN11 were searched from 2000 to 2022.
We present a case of a proband with a PTPN11 variant (c.1492C > T/p.Arg498Trp) inherited from an asymptomatic father, displaying only mild intellectual disability without classical symptoms of NS. Among our cases and the reported NS cases caused by the PTPN11 p.Arg498Trp variant, cardiac abnormalities (6/11), facial dysmorphism (7/11), skin pigmentation (4/11), growth problems (4/11), and sensorineural hearing loss (2/11) have been observed. NS/NSML patients with the PTPN11 p.Arg498Trp variant tend to exhibit relatively lower frequencies of skin pigmentation, facial dysmorphism and cardiac abnormalities and mild symptoms compared to those carrying any other mutated PTPN11.
Paternally inherited NS/NSML caused by a PTPN11 p.Arg498Trp variant, including our cases, may exhibit relatively lower frequencies of abnormal features and mild symptoms. This could be ascribed to potential gene-gene interactions, gene-environment interactions, the gender and phenotype of the transmitting parent, or ethnic differences that influence the clinical phenotype.

A rare case of autosomal dominant spastic paraplegia in a 36-year-old female with two reported earlier mutations of most common spastic paraplegia forms: SPG4 (mutation p.Cys28Leufs*20 in SPAST gene) and SPG3 (mutation p.Val405Met in ATL1 gene) is presented. The mutations detected by massively parallel sequencing (MPS) panel were inherited from affected mother and clinically unaffected father, respectively. The proband, her 61-year-old mother and deceased grandfather had \'uncomplicated\' paraplegia with onset in 4th decade. The 67-year-old father had no even minimal subclinical signs of the disease and no affected relatives, detection of his low-penetrating ATL1 mutation was unexpected. MPS methods are the most informative for identifying a patient and/or family members with a combined hereditary neurological pathology, especially a combination of similar forms of heterogeneous groups, such as spastic paraplegia.
Описан редкий случай аутосомно-доминантной спастической параплегии у женщины-пробанда 36 лет с выявленными с помощью высокопроизводительного экзомного секвенирования ранее описанными гетерозиготными мутациями двух генов самых частых форм: SPG4 (мутация p.Cys28Leufs*20 в гене SPAST) и SPG3 (мутация p.Val405Met в гене ATL1), унаследованными соответственно от больной матери и клинически здорового отца. Пробанд и 61-летняя мать, а также умерший дед имели картину «неосложненной» параплегии с началом на 4-м десятилетии. У 67-летнего отца не было даже субклинических симптомов болезни, отягощенность в его ветви семьи не прослеживалась, обнаружение отцовской мутации с низкой пенетрантностью стало неожиданным. Методы MPS наиболее информативны для выявления у больного и/или членов семьи комбинированной наследственной неврологической патологии, особенно сочетания сходных форм гетерогенных групп, таких как спастические параплегии.

The SMARCC1 gene has been involved in congenital ventriculomegaly with aqueduct stenosis but only a few patients have been reported so far, with no antenatal cases, and it is currently not annotated as a morbid gene in OMIM nor in the Human Phenotype Ontology. Most of the reported variants are loss of function (LoF) and are often inherited from unaffected parents. SMARCC1 encodes a subunit of the mSWI/SNF complex and affects the chromatin structure and expression of several genes. Here, we report the two first antenatal cases of SMARCC1 LoF variants detected by Whole Genome Sequencing (WGS). Ventriculomegaly is the common feature in those fetuses. Both identified variants are inherited from a healthy parent, which supports the reported incomplete penetrance of this gene. This makes the identification of this condition in WGS as well as the genetic counseling challenging.

We describe a case of young onset generalized dystonia, harboring a previously unreported likely pathogenic THAP1 missense variant (c.109 G > A; p.Glu37Lys) that was inherited from her unaffected father. Moreover, we report a positive effect of deep brain stimulation, particularly on the cervical component of dystonia.

UNASSIGNED: Rare genetic variants have been identified to be important contributors to the risk of Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease (CHD). But relatively limited familial studies with small numbers of TOF cases have been reported to date. In this study, we aimed to identify novel pathogenic genes and variants that caused TOF in a Chinese family using whole exome sequencing (WES).
UNASSIGNED: A Chinese family whose twins were affected by TOF were recruited for this study. A WES was performed for the affected twins, their healthy brother, and parents to identify the potential pathogenic mutated gene(s). Heterozygous variants carried by the twins, but not the unaffected brother, were retained. Public databases were used to assess the frequencies of the selected variants, and online prediction tools were accessed to predict the influences of these variants on protein function. The final candidate variant was further confirmed by Sanger sequencing in other members of the family.
UNASSIGNED: After several filtering processes, a heterozygous missense variant in the MYOM2 gene (NM_003970.4:c.3097C>T:p.R1033C) was identified and confirmed by Sanger sequencing in the affected twins and their unaffected father, suggesting an inheritance pattern with incomplete penetrance. The variant was found to be extremely rare in the public databases. Furthermore, the mutated site was highly conserved among mammals, and as shown using multiple online prediction tools, this variant was predicted to be a detrimental variant.
UNASSIGNED: We assessed a family with TOF caused by a rare heterozygous missense variant of MYOM2. Our findings not only further confirm the significant role of genetics in the incidence of TOF but also expand the spectrum of the gene variants that lead to TOF.

Lynch syndrome (LS) is a cancer-predisposing genetic disease mediated by pathogenic mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. Accumulating evidence demonstrates that there is significant biological heterogeneity across MMR genes. Compared to MLH1 and MSH2, PMS2 variant carriers have a much lower risk for LS-related cancers. Tumors in MLH1 and MSH2 variant carriers often display MMR deficiency (dMMR) and/or high microsatellite instability (MSI-H), two predictive biomarkers for immunotherapy efficacy. However, tumors in PMS2 variant carriers are largely microsatellite stable (MSS) instead of MSI. Therefore, the optimal management of cancer patients with LS requires the integration of disease stage, MMR gene penetrance, dMMR/MSI status, and tumor mutational burden (TMB). In this work, we presented a locally advanced lung cancer patient with dMMR/MSI-H/TMB-H tumor and selective loss of PMS2 by immunohistochemistry. Germline testing revealed a rare PMS2 splicing variant (c.1144+1G>A) in the proband and his healthy daughter. The diagnosis of LS was made based on genetic analysis of this variant and literature review. Given the incomplete penetrance of PMS2, the proband and the carrier received tailored genetic counseling. To reduce cancer risk, the proband received four cycles of nivolumab plus chemotherapy and achieved a disease-free survival of sixteen months.

Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare disease characterized by microangiopathic hemolysis, thrombocytopenia, and renal impairment and is associated with dysregulation of the alternative complement pathway on the microvascular endothelium. Outcomes have improved greatly with pharmacologic complement C5 blockade. Abnormalities in complement genes (CFH, CD46, CFI, CFB, C3, and THBD), CFH-CFHR genomic rearrangements, and anti-FH antibodies have been reported in 40-60% of cases. The penetrance of aHUS is incomplete in carriers of complement gene abnormalities; and multiple hits, including the CFH-H3 and CD46 GGAAC risk haplotypes and the CFHR1 * B risk allele, as well as environmental factors, contribute to disease development. Here, we investigated the determinants of penetrance of aHUS associated with CD46 genetic abnormalities. We studied 485 aHUS patients and found CD46 rare variants (RVs) in about 10%. The c.286+2T>G RV was the most prevalent (13/485) and was associated with <30% penetrance. We conducted an in-depth study of a large pedigree including a proband who is heterozygous for the c.286+2T>G RV who experienced a severe form of aHUS and developed end-stage renal failure. The father and paternal uncle with the same variant in homozygosity and six heterozygous relatives are unaffected. Flow cytometry analysis showed about 50% reduction of CD46 expression on blood mononuclear cells from the heterozygous proband and over 90% reduction in cells from the proband\'s unaffected homozygous father and aunt. Further genetic studies did not reveal RVs in known aHUS-associated genes or common genetic modifiers that segregated with the disease. Importantly, a specific ex vivo test showed excessive complement deposition on endothelial cells exposed to sera from the proband, and also from his mother and maternal uncle, who do not carry the c.286+2T>G RV, indicating that they share a circulating defect that results in complement dysregulation on the endothelium. These results highlight the complexity of the genetics of aHUS and indicate that CD46 deficiency may not be enough to induce aHUS. We hypothesize that the proband inherited from his mother a genetic abnormality in a complement circulating factor that has not been identified yet, which synergized with the CD46 RV in predisposing him to the aHUS phenotype.

Aim of this work was to describe a rare inheritance pattern of Primary Failure of Eruption (PFE) in a small family with incomplete penetrance of PFE and a novel nonsense PTH1R variant.
The proband, a 26 year-old man with a significant bilateral open-bite, was diagnosed with PFE using clinical and radiographic characteristics. DNA was extracted from the proband and his immediate family using buccal swabs and the entire PTH1R coding sequence was analyzed, revealing a novel heterozygous nonsense variant in exon 7 of PTH1R (c.505G > T). This variant introduces a premature stop codon in position 169, predicted to result in the production of a truncated and non-functional protein. This variant has never been reported in association with PFE and is not present in the Genome Aggregation Database (gnomAD). Interestingly, the c.505G > T variant has also been identified in the unaffected mother of our proband, suggesting incomplete penetrance of PFE.
In this study, we report a new PTH1R variant that segregates in an autosomal dominant pattern and causes PFE with incomplete penetrance. This underlines the diagnostic value of a thorough clinical and genetic analysis of all family members in order to estimate accurate recurrence risks, identify subtle clinical manifestations and provide proper management of PFE patients.

Familial hypercholesterolemia (FH) is a genetic disease associated with persistently elevated levels of low-density lipoprotein cholesterol (LDL-C), which ultimately leads to greatly increased rates of atherosclerosis and cardiovascular disease. Atherosclerosis progression can be clinically approximated through measurement of coronary artery calcification (CAC). CAC can be measured via electron beam computed tomography (EBCT), multi-slice computed tomography (MSCT), or contrast-enhanced CT coronary angiography (CTCA). Here, we present the case of a 72-year-old man with known FH and established hypercholesterolemia who has consistently tested negative for any significant CAC.

We describe the case of one patient with pure sporadic hemiplegic migraine (SHM) with a novel ATP1A2 gene variant and a large patent foramen ovale (PFO) with atrial septal aneurysm. In hemiplegic migraine (HM), the relationship between incomplete penetrance, environmental triggers, and phenotypic expression is underdetermined. A genetic evaluation of the proband was requested for the HM associated genes and extended to the members of his family. Genetic analysis revealed a never described before ATP1A2 gene mutation, inherited by his father, who never experienced motor aura but only typical visual aura. The proband-but not his father-was also affected by a large PFO with atrial septal aneurysm. SHM patient showed a marked reduction in motor aura episodes per year in the 12 months following the PFO percutaneous closure, followed by a complete remission from attacks at least in the following 24 months. We speculated that as well as incomplete penetrance of the novel mutation and natural history of the disease, an additional pathological condition such as the PFO could contribute to the phenotypical expression in this case of HM.