Stratospheric ozone shields life on Earth from harmful ultraviolet radiation and plays a crucial role in climate formation, while tropospheric ozone is a pollutant and greenhouse gas. Satellite methods based on measurements of outgoing thermal radiation are the only methods that provide information on global ozone distribution, independent of solar illumination. Since about 90% of atmospheric ozone is concentrated in the stratosphere, ozone total column measurements can be used as stratospheric ozone measurements. We present techniques for deriving information on total ozone columns (TOCs) and tropospheric ozone columns (TrOCs) from spectra of outgoing thermal radiation measured by the IKFS-2 instrument aboard the Meteor-M No. 2 satellite. The techniques are based on principal component analysis and the artificial neural network approach, providing high accuracy in TOC (less than 3%) and TrOC (within 2–4 DU) retrieval in accordance with the WMO requirements for the quality of satellite measurements.

Proximal spinal muscular atrophy 5q (SMA 5q) is a severe autosomal recessive neuromuscular disease characterized by progressive symptoms of flaccid paralysis and muscular atrophy due to degeneration of α-motor neurons of the anterior horns of the spinal cord. To date, the main modifying factor of spinal muscular atrophy is considered to be the number of copies of the SMN2 gene. However, a sufficient number of other genetic and non-genetic modifiers of the course of SMA have been described.Advanced neonatal screening, which started in the Russian Federation in 2023, allows detecting SMA 5q before the onset of clinical manifestations. However, to start therapy and select the right drug, it is important to know not only the main modifying factor (the number of copies of SMN2), but also other genetic causes that may affect the age of the disease manifestation or the effectiveness of therapy.

Inherited retinal diseases (IRDs) are a clinically heterogeneous group of retinal pathologies associated with vision loss due to dysfunction or degeneration of photoreceptor and retinal pigment epithelium. Autosomal recessive forms of IRDs account for more than 55% of all diseases in this group on average worldwide. This study presents data on frequent pathogenic and likely pathogenic variants in recessive IRDs genes obtained from a retrospective analysis of high-throughput sequencing data from a large Russian cohort of patients with suspected hereditary non-syndromic retinal pathology. Data from 1470 unrelated patients were analyzed. Pathogenic and likely pathogenic variants were identified in the zygosity required for the development of the diseasein 643 patients (43.74%). It was found that 9 genes (ABCA4, CNGB3, USH2A, RPE65, CRB1, CNGA3, CEP290, GUCY2D, PDE6H) account for 73.3% of all molecularly confirmed cases of IRDs in Russian patients. An analysis of the spectrum of nucleotide variants of these genes was carried out, and 17 variants were identified that occur with an allelic frequency of more than 1% for each gene. In light of obtained data, the diagnostic systems based on the multiplex ligation-dependent probe amplification reaction (MLPA) were developed. The informativity of the two systems for diagnosing autosomal recessive non-syndromic forms of inherited retinal diseases is 16.4%, the informativity for all forms of non-syndromic retinal diseases exceeds 7%. For a group of patients with achromatopsia, a study using one of the systems will make it possible to establish a diagnosis in 62.5% of cases.

Duchenne muscular dystrophy (DMD) is an orphan neuromuscular progressive genetic disease that causes muscle breakdown and subsequent loss. Provided early diagnosis, complex standard and pathogenetic therapy significantly changes the trajectory of the disease, making it more benign. Diagnosis of DMD is a two-pillar system with creatine kinase (CK) level measured at the first stage followed by molecular genetic study in case the enzyme threshold values. The quality of genetic diagnostics in Russia has reached the best worldwide standards recently though identifying children with elevated CK levels is yet difficult. The number of diagnosed DMD patients in Russia is significantly lower than the statistically estimated global amount. The average age for diagnosis is not decreasing either. Thus, the median age for DMD and Becker muscular dystrophy (BMD) molecular diagnosis is 7 years and 8 months old. The number of identified children below the age of 2 y/o in Russia has remained consistently low over the past three years. According to the results of a familial cases survey, the correct primary diagnosis of DMD was established in less than half of all cases, 47.1%. The most common incorrect diagnoses were as follows: asymptotic hepatitis (25.1%), perinatal damage to the central nervous system (6.4%), cerebral palsy (2.7%), autism spectrum disorder (ASD) (2.7%) and flat feet, hallux valgus etc. (16% in total). The median duration between the initial DMD manifestation and molecular diagnosis is 3 years and 8 months as yet whilst the age-specific guidelines suggest prescribing standard and pathogenetic therapy during the 2 to 5 y/o period of life. Therefore, the Russia’s average age of DMD diagnosis above 7 y/o lies far beyond the optimal age for initiating of the DMD therapy with the purpose of gaining its maximum possible clinical benefit. The accumulated international and Russian experience demonstrates the possibility for improving of the primary DMD and BMD diagnosis in early preschool age and therefore requires its nationwide introduction.

Background. Existing registries of patients with spinal muscular atrophy (SMA) 5q serve as a valuable source of information on identified patients. Information on the characteristics of Russian patients with SMA 5q and the therapy administered in real clinical practice is currently limited.Aim. To describe a cohort of Russian patients with a confirmed diagnosis of SMA 5q and to evaluate patient routing data in real clinical practice settings in Russia.Materials and methods. The present study was a descriptive non-interventional retrospective cohort study in patients diagnosed with SMA 5q who were enrolled in the Russian patient registry between January 1, 2020 and March 31, 2023. Study participants who met the inclusion criteria were automatically identified in the integrated database of the SMA 5q patient registry. Data were uploaded into validated electronic charts, verified and analyzed using descriptive statistics methods. Results. As of March 31, 2023, the Russian SMA registry contained information on 1408 patients from all federal districts and obtained epidemiological, sociodemographic and clinical characteristics of patients, as well as routes to diagnosis and treatment regimens for patients. The median time from disease onset to confirmed diagnosis was 3 months in patients with SMA type 1, 9 months in patients with SMA type 2, 20 months in patients with SMA type 3 and 68 months in patients with SMA type 4. The median time from confirmed diagnosis to the start of disease-modifying therapy was 0.5 months in SMA patients identified by neonatal screening, 21 months in patients with SMA type 1, 59 months in patients with SMA type 2, 47 months in patients with SMA type 3 and 87 months in patients with SMA type 4.Conclusion. This retrospective analysis was carried out in order to identify recent approaches to the diagnosis and treatment of SMA used in real-world clinical practice in Russia. The identified parameters (duration from the disease onset to confirmed diagnosis, duration from the confirmed diagnosis to disease-modifying therapy initiation) indicate that more widespread use of newborn screening and more rapid treatment initiation are unmet needs for SMA patients in Russia.

IntroductionBardet–Biedl syndrome is a rare condition characterized by obesity, retinitis pigmentosa, polydactyly, development delay, and structural kidney anomalies. This syndrome has an autosomal recessive type of inheritance. For the first time, molecular genetic testing has been provided for a large cohort of Russian patients with Bardet–Biedl syndrome.Materials and methodsGenetic testing was provided to 61 unrelated patients using an MPS panel that includes coding regions and intronic areas of all genes (n = 21) currently associated with Bardet–Biedl syndrome.ResultsThe diagnosis was confirmed for 41% of the patients (n = 25). Disease-causing variants were observed in BBS1, BBS4, BBS7, TTC8, BBS9, BBS10, BBS12, and MKKS genes. In most cases, pathogenic and likely pathogenic variants were localized in BBS1, BBS10, and BBS7 genes; recurrent variants were also observed in these genes.DiscussionThe frequency of pathogenic and likely pathogenic variants in the BBS1 and BBS10 genes among Russian patients matches the research data in other countries. The frequency of pathogenic variants in the BBS7 gene is about 1.5%–2% of patients with Bardet–Biedl syndrome, while in the cohort of Russian patients, the fraction is 24%. In addition, the recurrent pathogenic variant c.1967_1968delinsC was detected in the BBS7 gene. The higher frequency of this variant in the Russian population, as well as the lack of association of this pathogenic variant with Bardet–Biedl syndrome in other populations, suggests that the variant c.1967_1968delinsC in the BBS7 gene is major and has a founder effect in the Russian population. Results provided in this article show the significant role of pathogenic variants in the BBS7 gene for patients with Bardet–Biedl syndrome in the Russian population.

Background. Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in children, that occurs between one and three years of age. DMD is caused by pathogenic and likely pathogenic variants in the DMD gene, which lead to a deficit of various isoforms of the dystrophin protein, the main protein of the muscle cytoskeleton. Drugs aimed at slowing the progression of the disease are being actively developed around the world. One of the perspective approaches to pathogenetic therapy is therapy using exon skipping. As a result of this treatment, the reading frame is restored due to the exon skipping enabling the production of truncated dystrophin.Aim. To evaluate the applicability of exon skipping therapy in Russian patients with DMD.Materials and methods. The applicability of therapy aimed at exon skipping was analyzed for a sample of 1519 patients admitted to the laboratory of DNA diagnostics of the Research Centre for Medical Genetics with a referral diagnosis of Duchenne/Becker muscular dystrophy from October 1, 2018 to September 1, 2023.Results. As a result of the study and analysis of the spectrum of mutations in the DMD gene among patients with DMD in the Russian Federation, the theoretical applicability of exon skipping therapy was assessed: for 29.3 % of patients this approach to treatment is applicable. The proportions of patients for whom existing exon skipping therapies are available were also estimated. In total, skipping of frequent exons 51, 53, 45 is applicable for 14.6 % of patients. Conclusion. One of the effective and accessible types of therapy for DMD is exon skipping. This type of therapy is mutation-specific. In this regard, the assessment of applicability will allow us to estimate the proportion of patients for whom a particular exon skipping will be available.

Duchenne muscular dystrophy is a genetic orphan neuromuscular disease caused by a mutation in the DMD gene encoding the protein dystrophin. As a result of developing and progressive muscle damage and atrophy, children lose the ability to walk, develop respiratory and cardiac disorders. The core elements of good care standards are early diagnosis, prevention and treatment of osteoporosis, daily physical therapy, regular rehabilitation, glucocorticosteroids, and control of heart and lung function. The clinical effect of new targeted pathogenetic therapies for Duchenne muscular dystrophy, restoring synthesis of full or truncated dystrophin, depend on their appropriate combination with existing standards of care.

Objectives: Russian Cystic Fibrosis Patient Registry (RCFPR) analysis is a tool to assess the status of DNA diagnosis, characterise new pathogenic variants of the CFTR gene, plan DNA screening measures and prescribe targeted therapies. Aim - to analyze the allelic frequency of CFTR gene variants in the Russian Federation and the status of molecular diagnostics over 11 years. Methods: The data of DNA diagnosis of CF patients on the basis of the RCFPR from 2011 to 2021 were analyzed. Results: An increase in the total number of patients from 1026 in 2011 to 3969 in 2021, an increase in coverage by genetic examination from 91.8% to 93.6%, an increase in the number of detected mutations from 80% to 90.5%, a decrease in the number of patients with undetected mutations from 9.5% to 3.2% were revealed. The number of pathogenic variants detected increased from 73 in 2011 to 240 in 2021. Among the 10 most frequent CFTR gene variants: F508del, CFTRdele2,3, E92K, 1677delT>A, 3849+10kbC>T, 2143delT, 2184insA, W1282X, L138ins, N1303K. The pathogenic variants F508del (52.79%/51.55%) and CFTRdele2,3 (6.32%/6.11%) remained in the first two positions (2011/2021). In third place was the "Chuvash mutation" E92K (2.65%/3.46%). The "Caucasian" mutation 1677delT>A (2.25%) ranked fourth in 2021, while in 2011 it was not on the list of 10 frequent pathogenic variants. Fifty-eight undescribed variants of the CFTR gene were identified. In 2021 the allele frequency of p.[F508del;L467F] complex allele was 0.86% (8.12% among F508del homozygous patients in whom the presence of this complex allele in the genotype prevents response to lumacaftor/ivacaftor treatment); the frequency of p.[S466X;R1070Q] complex allele was 0.59%. Conclusion: Thanks to the RCFPR the allelic frequency of CFTR gene variants in Russia has been established. Dynamics of DNA diagnosis showed an improvement in the organization of DNA diagnosis. The impact of complex alleles should be considered when planning targeted therapy.

Background . Spinal muscular atrophy (SMA) is a severe rare disease that has been widely discussed in recent years. Achievements in etiopathogenetic therapy and the social significance of the disease (child population, high mortality), the cost of treatment attracted the attention of the public and the goverment, which, among other things, led to the formation of a separate area with the creation of a fund to finance the treatment of patients with orphan diseases. Aim . To conduct an analysis of the socio-economic efficiency of mass neonatal screening for SMA in the Russian Federation. Materials and methods . A survey of patients (their parents) and doctors was conducted. The current clinical guidelines and the standard of medical care for children with SMA were studied. The cost of medicines is taken from the State Register of Maximum Selling Prices. If the drug is not included in the List of Vital Essential and Necessary Drugs, cost information from the procurement data is used. Results . The socioeconomic burden of SMA on identified patients was about 3,994,289,548 rubles per year prior to screening. The very introduction of mass neonatal screening will amount to about 679,224,000 rubles in year. At the same time, a disease detected in a timely manner due to neonatal screening and timely prescribed effective treatment can lead to a reduction in the cost of specialized and palliative care by 54,073,271 rubles, direct non-medical costs by 88,137,423 rubles, and indirect costs by 154,197,900 rubles per year, which together is more than 7 % of the calculated burden of SMA. Conclusion . The introduction of mass screening will lead to the fact that the number of annually detected patients will increase from current values to the actual value of the prevalence when registering patients with milder forms of SMA. The need for drug supply with drugs and medical care in general will increase. At the same time, children diagnosed with SMA will not die in the early years of life, their survival rate, life expectancy will increase, the quality of life will improve, infant mortality will decrease, which is the main task of neonatal screening and one of the goals of the National Healthcare Project.

Background . Duchenne muscular dystrophy (DMD) is a severe, progressive form of muscular dystrophy that occurs in children between one and three years of age. The disease is mainly characterized by weakness of the proximal muscles, which leads to difficulty in movement, and ultimately to complete disability. Becker muscular dystrophy (BMD) is a milder allelic form of the disorder characterized by late onset and slow progression. The cause of the development of DMD/BMD is mutations in the DMD gene, leading to a deficiency in the production of various isoforms of the dystrophin protein family. The most common mutations in case of DMD/BMD are gross deletions (55–65 %) and duplications (6–11 %) of one or several exons The remaining cases of DMD/BMD are due to small mutations (approximately 20–30 %). Depending on the methodological capabilities of the laboratory, the idea of the spectrum of mutations in the DMD gene changed, which is important in genetic counseling of patients and planning the therapy available today. Aim . To analyze the spectrum of mutations in the DMD gene, including three time slices, depending on the methodological capabilities of the laboratory. Materials and methods . We analyzed the spectrum of mutations in the DMD gene for a sample of 2957 patients admitted to the laboratory of DNA diagnostics of the Research Centre for Medical Genetics with a referral diagnosis of DMD/BMD. Depending on the time of treatment and the capabilities of the laboratory, patients were divided into three groups: 2008–2015, 2016–2018, 2019–2022. Results . As a result of the study, the full range of mutations in the DMD gene was analyzed over three-time intervals, which makes it possible to get an idea of the distribution of mutation types in the sample among Russian patients. Regardless of the methodological capabilities of the laboratory, the spectrum of mutations in the DMD gene remains biased relative to world data. At the moment, there is a significant decrease in the proportion of extended deletions (50.7–59.6 %), while the proportion of extended duplications (11.8–17.2 %) and small mutations (23.2–35.0 %) increased. We assume that the main reason for such features of the spectrum is ethnic and population differences. Conclusion . Duchenne/Becker muscular dystrophy (DMD/BMD) is the most common form of muscular dystrophy, accounting for more than 50 % of all cases. Determination of the spectrum of mutations provides an understanding of their frequencies, which in the future may help patients in the appointment of therapy specific to a particular type of mutation.

Background . 46,XX male syndrome (XX sex reversal) or 46,ХХ testicular disorder of sex development (DSD) – a genetic disorder that characterized by primary hypogonadism and male infertility because of severe spermatogenesis defects. 46,XX testicular DSD is resulted from unbalanced microstructural sex chromosome abnormalities, mostly X-Y translocations involving SRY gene. Genetic heterogeneity and phenotypic variability, particularly the effect of the genotype on semen parameters in XX sex reversed patients are not sufficiently studied. Aim . Genetic and semen examination in patients with 46,ХХ testicular DSD. Materials and methods . 32 patients with 46,XX testicular DSD and 2 men with mosaicism 46,XX/46,XY were examined. Cytogenetics, molecular genetics and spermatology examination (standard semen analysis and quantitative karyological analysis of immature germ cells) were performed. Results . The presence of the SRY gene was detected in 23 (82.1 %) of 28 patients who underwent a molecular genetic study, and 5 patientswere SRY -negative. Azoospermia and severe oligozoospermiawere diagnosed in 24 (75 %) and 8 (25 %) patients, respectively. Quantitative karyological analysis of immature germ cells allowed to reveal cryptozoospermia in 3 patients with initially diagnosed azoospermia (according to a standard semen analysis). Severe oligozoospermia and cryptozoospermia were mentioned both in some of SRY -positive and SRY -negative patients. Conclusion . 46,XX testicular DSD is characterized by severe degree of spermatogenesis defects (azoospermia and extremely severe oligozoospermia). Small number of germ cells detected in ejaculate in some patients with 46,XX testicular DSD, including SRY -negative individuals, indicates partial preservation ofspermatogenesisin the absence of Y chromosome genes.

The pattern of microdeletions of the long arm of the Y chromosome in the AZFb region was determined among 165 men with infertility. AZFb deletions were found in 25 % of them, of which complete AZFb deletions (P5/proximal P1, P4/proximal P1) accounted for 22 %, partial AZFb deletions — 3 %. AZFb+c deletions in 75 % of patients, of which complete AZFb+c were 98 %, partial AZFb + complete AZFc were 2 %. Breakpoints allowed us to clarify the size and localization of deletions capturing the palindromic region of the Y chromosome for 55 samples.

Supplement to the 2023 Issue 6 (Volume 102) of the Journal PEDIATRIA named after G.N. Speransky. Guidelines for Practitioners: Duchenne Muscular Dystrophy (DMD). Becker Muscular Dystrophy (BMD). Early diagnosis. Therapy with the use of drugs that are currently not registered properly in Russia/by the Ministry of Healthcare of Russia. DOI: 10.24110/0031-403X-2023-102-6-217-256. https://doi.org/10.24110/0031-403X-2023-102-6-217-256

For citation: A.I. Asmanov, N.D. Vashakmadze, V.A. Vilensky, V.Yu. Voinova, I.G. Vorontsova, I.S. Dantsev, N.V. Zhurkova, T.N. Kekeyeva, V.M. Kenis, T.T. Knyazeva, T.V. Markova, L.K. Mikhailova, E.V. Nagaeva, P.V. Ochirova, E.E. Petryaykina, A.V. Polyakov, D.A. Popkov, E.A. Putilina, D.A. Reshchikov, I.G. Rybkina, S.O. Ryabykh, M.O. Saghatelyan, L.V. Toropchina, A.N. Tiulpakov. Russian interdisciplinary consensus on achondroplasia (approved by the Expert Council in Jan. 2023). Pediatria n.a. G.N. Speransky. 2023; 102 (3): 151-157. DOI: 10.24110/0031-403X-2023-102-3-151-157.

Rubinstein–Taybi syndrome is a multisystem pathology characterized by mental retardation and delayed physical development in combination with a set of phenotypic features, which make up a recognizable pattern of the disease. This review of the literature highlights the molecular‑genetic basis and the presumed pathogenesis of the Rubinstein–Taybi syndrome, considers questions of geno‑phenotypic correlations and differential diagnosis in the group of pathologies called chromatinopathies.

Purpose: to evaluate the results of gene therapy by the recombinant adeno-associated viral vector voretigene neparvovec (VN) in children with follow-up periods of 1, 3, 6, and 12 months.Material and methods. The study included 6 children (12 eyes) aged 5 to 15 with a confirmed biallelic mutation in the RPE65 gene, treated with VN (Luxturna, USA). Treatment efficacy was assessed by surveying which included questions on spatial orientation under various types of illumination, Goldman perimetry, microperimetry, best corrected visual acuity (BCVA), electroretinogram (ERG), and visual evoked potentials (VEP). To assess the structure of the retina, the central retinal thickness (CRT) was evaluated by optical coherence tomography.Results. All children showed subjective changes in visual perception, including improved orientation in the dark and twilight, and improved contrast. In one case, the child with initially low visual acuity showed improved visual fixation. In 4 patients out of 6 (8 eyes), an expansion of the visual fields was noted, including 2 cases who displayed significant expansion thereof. In 2 patients (4 eyes), the visual fields were not narrowed and remained so throughout the entire observation period. Mean light sensitivity of the retina in 3 patients and fixation indices in 1 patient improved significantly as shown by microperimetry. BCVA remained stable throughout the study or changed insignificantly. Initially, ERG could not be detected in 8 eyes, but after an VN injection, 6 eyes demonstrated a partial recovery at different times — from 1 to 12 months. An increase in the amplitude of the P1 component to pattern VEP and P2 component to flash VEP was observed in all patients, which indicates an enhanced activity in the projection of the visual cortex after the restoration of the visual cycle. No significant changes were revealed in CRT (p = 0.9). Complications and adverse events were noted in 9 eyes (75 %): chorioretinal dystrophy at the injection site in 3 patients (5 eyes), multifocal nummular dystrophy in 2 patients (4 eyes), local episcleritis in 1 eye, transient increase in intraocular pressure in 2 patients (3 eyes).Conclusion. The results of a one-year post VN treatment follow-up of Russian patients with RPE65-associated inherited retinal disease demonstrate stabilization and improvement of visual functions, which is especially important for otherwise incurable patients with a progressive course of the disease.

Background . Among the syndromes with aneuploidy on the sex chromosomes (gonosomes), the Y chromosome dysomy presents the mildest phenotypic manifestation. Most 47,XYY patients are not developed reproductive system abnormalities. Some of them have spermatogenesis defects and in-/subfertility, but the prevalence of male infertility in patients with dysomy Y, is not known. The causes and factors of phenotypic variability, fertility disorders, the spermatogenesis and semen characteristics in patients with dysomy Y have not been sufficiently studied. Aim . A comprehensive genetic examination, assessment of the state of spermatogenesis and spermatological defects in patients with dysomy Y. Materials and methods . We examined 25 men with Y-chromosome dysomy. The age of the patients was 32 ± 10 (14–59) years. Chromosome analysis was performed on cultured peripheral blood lymphocytes using a standard cytogenetic method with GTG-staining. Fluorescent in situ hybridization was performed to analyze X and Y chromosomes, gonosomal mosaicism, as well as to evaluate sperm aneuploidy. The Y chromosome microdeletions were detected by multiplex polymerase chain reaction. A standard semen analysis was performed in accordance with the recommendations of the WHO Guidelines (2010). Quantitative karyological analysis of immature germ cells from the ejaculate sediment was performed according to our own previously developed method. Results . Non-mosaic dysomy Y was diagnosed in 22 patients, including 21 men with karyotype 47,XYY, and one patient with additional chromosomal anomality (Robertson translocation) – karyotype 46,XYY,der(13;14)(q10;q10). XYY/XY mosaicism was revealed in two patients, one has a complex Y chromosome mosaicism with a complete the AZFc (b2/b4) deletion. Pathogenic Y chromosome microdeletions were not found in other patients. In one man, the presence of dysomy Y was suspected according to the results of quantitative fluorescent polymerase chain reaction, but according to the results of cytogenetic examination, the presence of an isodicentric chromosome Yq – karyotype 46,X,psu dic(Y)(p11.3) was detected. Using whole exome sequencing in one azoospermic patient, a heterozygous variant c.653G>A(p.Gly218Asp) was detected in the SYCP2 gene, which encodes one of the proteins of the synaptonemal complex. Azoospermia (n = 9, 45 %), oligoastenoteratozoospermia (n = 6, 39 %), asthenoteratozoospermia (n = 3, 17 %), and asthenozoospermia (n = 2, 11 %) were diagnosed among 20 semen analysed patients. The volume of ejaculate was 2.7 ± 1.7 (1.0–5.0) ml, the concentration and total number of spermatozoa was 14.9 ± 21.8 (0.0–66.25), 50.4 ± 77.7 (0.0–265.0) mil lions, respectively. Oligospermia was observed in 2 (10%) patients. The quantitative karyological analysis of immature germ cells allowed to detect cryptozoospermia in azoospermic patinents and defects of prophase I of meiosis. Fluorescent in situ hybridization analysis revealed increased sperm aneuploidy (gonosomal dysomy and nullisomy, dysomy 18 and 21). Conclusion . Most of infertile men with dysomy Y are non-mosaic, and characterized by defected spermatogenesis (non-obstructive azoospermia or oligozoospermia), due to meiotic arrest at prophase I. Pathogenic AZFc deletion was found in a patient with complex Y chromosome mosaicism. Additional genetic factors of male fertility and spermatogenesis defects were found in some patients, which may explain the phenotypic variability.