Patterns of Inheritance: Mendelian and Non-Mendelian
Merlin G. Butler, F. John Meaney in Genetics of Developmental Disabilities, 2019
There are some exceptions to the “rules” of autosomal dominant inheritance mentioned above. Some autosomal dominant genetic diseases do not clearly follow a vertical transmission pattern due to reduced penetrance. Penetrance is the probability that a disease gene will have a phenotypic expression. A trait is 100% penetrant if every individual with a disease-causing gene is affected and shows features of the autosomal dominant condition. Achondroplasia is an example of a condition with 100% penetrance. A genetic disease shows reduced penetrance when an individual who has the disease-causing gene does not exhibit the disease phenotype, but can still pass on the disease-causing gene to the next generation. The phenomenon of reduced penetrance is one explanation for a trait that seems to “skip” generations.
Neurological conditions
David M. Luesley, Mark D. Kilby in Obstetrics & Gynaecology, 2016
Multiple sclerosis (MS) is a multifocal autoimmune disease of the CNS. Infiltrating lymphocytes and macrophages bring about inflammation, demyelination and axonal damage while further activating inherent CNS immune cells such as astrocytes and microglia. Optic nerve, brain and spinal cord may all be affected and this may manifest as almost any neurological deficit, symptom or sign. Most cases are characterised by a ‘relapsing and remitting’ natural history, with slow gradual decline. Less commonly, the MS follows a more rapidly progressive pattern. Diagnoses of MS are either ‘probable’ or ‘definite’, depending on whether the clinical features (probable) have been supported by the results of specialised investigations (oligoclonal abnormalities in cerebrospinal fluid, white matter lesions on MRI or prolonged latency of evoked potentials on neurophysiological testing). An inheritable genetic element to the disease does exist, but very rarely is a true mendelian pattern of autosomal dominance seen. Overall, the risk of the offspring developing MS with one affected parent appears to be approximately 4 percent. The rate can, however, be as high as 30 percent if both parents are affected [D]. Viral infection is likely to be a more important aetiological factor and indeed relapses are more common following non-specific viral illness [D].
Severe male factor infertility: Genetic consequences and recommendations for genetic testing
David K. Gardner, Ariel Weissman, Colin M. Howles, Zeev Shoham in Textbook of Assisted Reproductive Techniques, 2017
Very rarely, patients with other mostly syndrome- associated genetic defects may consult at a male infertility clinic. Up to 80% of patients with Noonan syndrome present with oligozoospermia or azoospermia as a result of cryptorchidism (67). The diagnosis is so far based on other symptoms, including small stature, chest deformity, a rather typical facial dysmorphism, and congenital heart disease. Defects in a gene on chromosome 12q24.1, PTPN11, are responsible for approximately 40% of patients with Noonan syndrome (68). Another six genes involved in Noonan syndrome have been identified; all seven known genes account for around 60% of cases. Consequently, more (currently unknown) genes are involved in Noonan syndrome. The autosomal dominant inheritance asks for genetic counseling. Other possible patients may be affected by Aarskog-Scott syndrome with acrosomal sperm defects (69, 70) or Beckwith-Wiedemann syndrome with cryptorchidism (71). Syndromes such as Bardet-Biedl syndrome and Prader-Willi syndrome, both presenting with hypogonadism, are associated with other major symptoms, including (severe) mental retardation, which limit procreation (72–74). Prader-Willi syndrome is an imprinting syndrome resulting from the absence of expression of the paternal alleles in the 15q11-q13 imprinted region (75–77). Other causes of male infertility include deficiencies in enzymes involved in the synthesis of testosterone (64, 66), luteinizing hormone, and luteinizing hormone receptor (78, 79).
A special case of hypertrophic cardiomyopathy with a differential diagnosis of isolated cardiac amyloidosis or junctophilin type 2 associated cardiomyopathy
Published in Acta Clinica Belgica, 2021
Sévérine De Bruijn, Xavier Galloo, Gilles De Keulenaer, Edgard A. Prihadi, Christiane Brands, Mark Helbert
In ATTR, the hepatic transport protein TTR, previously called prealbumin, is misfolded into an amyloid protein. TTR-related CA accounts for 18% of all cases of CA and is characterised by a progressive infiltrative cardiomyopathy that mimics hypertensive hypertrophic heart disease [7]. Transthyretin amyloidosis encompasses two subtypes. The hereditary/familial type (mATTR) – also called mutant type – arises from misfolding a mutated TTR precursor protein. It is characterized by autosomal dominant inheritance with variable penetrance. In sporadic or wild type (wtATTR), formally also known as senile systemic amyloidosis (SSA), amyloid arises from genetically unaltered TTR [9]. In contrast to AL amyloidosis, mATTR and wtATTR are typically associated with milder clinical manifestations, slower progression, and hence also better prognosis. Since the very slow progression (an 86-your-old patient) and mild clinical presentation (general fatigue with only mild decreased systolic function and no overt clinical heart decompensation) the differential diagnosis of an AL amyloidosis is very improbable based on anamnesis and physical exam. Further work-up confirmed normal immunoglobulin light chains. Arguments in favour of an ATTR are elderly patient, male, slow progression and mild clinical symptoms. As the patient described above only presents cardiac manifestations without altered kidney or liver function, the preferred differential diagnosis of wtATTR is withheld over mATTR.
Congenital alacrima
Published in Orbit, 2022
Zhenyang Zhao, Richard C. Allen
Branching morphogenesis is a key embryonic process for developing the tree-like architecture of multiple organs including lacrimal and salivary glands. Mesenchymal expression of fibroblast growth factor 10 (FGF10) is necessary for lacrimal gland development through interaction with its ligand, fibroblast growth factor receptor 2 (FGFR2), localized to the epithelium.63 Allelic heterogeneity of FGF10 mutations cause both aplasia of the lacrimal and salivary glands (ALSG) and lacrimo-auriculo-dento-digital (LADD) syndrome. Additional causative mutations in FGFR2 or FGFR3, are also identified in LADD,64 which covers a wider spectrum of malformations, including the dental, auditory, and digital abnormalities. Both conditions follow an autosomal dominant inheritance. Involvement of the lacrimal excretory apparatus is frequently reported, including hypoplastic or aplasia of puncta, nasolacrimal duct obstruction and dacryocystocele.29,30,32 Oculofacial features such as telecanthus, hypertelorism and congenital ptosis are found in LADD but absent in ALSG.
Histopathology of the Conduction System in Long QT Syndrome
Published in Fetal and Pediatric Pathology, 2022
Alexandra Rogers, Rachel Taylor, Janet Poulik, Bahig M. Shehata
There has also been evidence suggesting that JLNS could be inherited in an autosomal dominant fashion. This was demonstrated by Sanyal et al., who spent 16 years tracking the inheritance of JLNS in a family of 66 blood relatives. Results demonstrated that in families where one parent was diagnosed with JLNS, nearly 70% of offspring were also affected. Comparatively, in families where neither parent was afflicted, 0% of offspring had JLNS [7]. The significantly increased rate of successive generational affliction suggests an autosomal dominant inheritance. These findings were corroborated by Splawski et al. who postulated an autosomal dominant mode of inheritance for JLNS with an autosomal recessive inheritance pattern for the associated sensorineural deafness [7]. Several other studies have also confirmed these data, however, no final consensus has been reached regarding the mode of inheritance of JLNS.