Genetic study of indirect inguinal hernia.

We performed a genetic analysis of 280 families with congenital indirect inguinal hernia ascertained in Shandong province. The multifactorial threshold model and segregation analysis were applied to these families to investigate the mode of inheritance of congenital indirect inguinal hernia. Our results indicate that congenital indirect inguinal hernia is not compatible with a multifactorial threshold model, and the frequent vertical transmission and high segregation ratio suggest autosomal dominant inheritance with incomplete penetrance and sex influence. Through further pedigree analysis of the multiple case families with at least two closely related affected members, we noted preferential paternal transmission of the disease gene, which might suggest the role of genomic imprinting in the aetiology of this condition.     

Isolated congenital anosmia with morphologically normal olfactory bulb in two Iranian families: a new clinical entity?

Congenital total loss of the sense of smell occurs as a part of a syndrome or isolated anosmia. Kallmann syndrome is the most well known congenital anosmia associated with hypogonadotropic hypogonadism. Isolated congenital anosmia (ICA) is a very rare condition and appears to be due to changes in the olfactory epithelium or to aplasia of the olfactory nerve, bulb, and tract. Here we report two unrelated Iranian families with ICA. One family consisted of nine affected members, and the other family contained three affected members. Clinical history, physical examination, and smell testing by intravenous injection of combined vitamins (Alinamin trade mark, Takeda Pharmaceutical Co. Ltd., Japan) confirmed the disease in each affected member. No signs of hypogonadism or other neurological disorders were observed in any affected members. Family analysis with the complete ascertainment method under assumption of the same condition in the two families suggested that the disease is not inconsistent with an autosomal dominant mode with incomplete penetrance. The inheritance in one family appears unusual, i.e., there were no affected individuals in the third generation. When only two upper generations in the family are concerned, the segregation ratio was 0.39 +/- 0.11. Male-to-male transmissions were observed and both sexes were affected in both families. Magnetic resonance imaging (MRI) of the olfactory bulb and sulcus revealed no evidence of morphological changes in all affected members, suggesting that these patients have either a defect in the olfactory epithelium or a functional defect in the olfactory cortex.     

Distal arthrogryposis type 1: Clinical analysis of a large kindred

We describe the clinical findings of 15 individuals in a large kindred affected with distal arthrogryposis type 1A (DA1A). The most consistent findings among individuals were overlapping fingers at birth, abnormal digital flexion creases, and foot deformities, including talipes equinovarus and vertical talus. There was marked intrafamilial variation in the expression of DA1A. Linkage mapping of the locus for DA1A suggests that the use of strict diagnostic criteria excludes unaffected individuals rigorously, but can produce incomplete ascertainment of affected individuals. In the context of an affected family, the range of phenotypes consistent with a diagnosis of DA1A needs to be expanded. © 1996 Wiley-Liss, Inc.     

Coarctation of the aorta, interrupted aortic arch, and hypoplastic left heart syndrome in three generations.

Five members in three generations of a family were affected by a congenital heart disease. Four of them had mild or severe coarctation of the aorta (CoA), either isolated or in association with other cardiac defects. Fetal echocardiography allowed prenatal diagnosis in one pregnancy at risk. This family suggests that a rare form of CoA could be the result of an autosomal dominant mutation with high penetrance and variable expressivity rather than polygenic inheritance.     

Autosomal dominant isolated (''uncomplicated'') microcephaly.

A large family (13 affected members in three generations) is reported in which isolated microcephaly occurred without any other dysmorphic or neurological abnormalities. The family pedigree confirms the autosomal dominant mode of inheritance with incomplete penetrance, including one example of male to male transmission and the occurrence of a non-manifesting heterozygote resulting in a 'skipped generation'. There is considerable variation in the phenotypic expression of autosomal dominant microcephaly. This isolated (uncomplicated) type of microcephaly should be distinguished from other well defined, dominantly inherited forms of microcephaly.     

A novel VEGFR3 mutation causes Milroy disease

Milroy disease, also known as primary congenital lymphedema, is a hereditary form of lymphedema with autosomal dominant inheritance. Individuals with Milroy disease are typically characterized by congenital onset of lymphedema of the lower limbs due to hypoplasia of the lymphatic vessels. The genetic basis of most cases of Milroy disease has not been established, although mutations in the vascular endothelial growth factor receptor VEGFR3 (FLT-4) are responsible for some cases with 17 mutations described to date. In this report, we describe a novel VEGFR3 mutation in exon 22 in a four-generation family in which congenital lymphedema segregates in an autosomal dominant manner. In addition to lymphedema, affected family members had other clinical manifestations associated with Milroy disease including hydrocele, ski jump toenails, large caliber veins, and subcutaneous thickening. We screened VEGFR3 for mutations which revealed a novel 3059A>T transversion in exon 22 resulting in Q1020L missense mutation in the second tyrosine kinase domain of VEGFR3. This mutant allele segregated with lymphedema among affected individuals with incomplete penetrance. This is the first report of an exon 22 mutation in Milroy disease.     

Identification of a complex congenital heart defect susceptibility locus by using DNA pooling and shared segment analysis

The identification of genetic loci involved in most forms of congenital heart disease has been hampered by the complex inheritance patterns of these disorders. Atrioventricular canal defects (AVCDs) are most commonly associated with Down syndrome, although non-syndromic cases also occur. Non-syndromic AVCDs have been attributed to multifactorial inheritance. However, the occurrence of a few kindreds with multiple affected individuals has suggested that a major genetic locus can account for the disorder in some families. We have used a combination of DNA pooling and shared segment analysis to perform a high density screen of the entire autosomal human genome in an extended kindred. In so doing, we have identified a genetic locus on chromosome 1 shared by all affected individuals. Our data demonstrate the existence of a congenital heart defect susceptibility gene, inherited as an autosomal dominant with incomplete penetrance, involved in AVCD. Furthermore, our data demonstrate the power of using key isolated kindreds in combination with high density genomic screens to identify loci involved in complex disorders such as congenital heart defects.      

Familial congenital brachial palsy

Eight relatives in a Sicilian family, including a sibship of 5, were affected with severe unilateral congenital brachial palsy (CBP) in a pattern suggesting autosomal dominant inheritance with reduced penetrance (6 cases affected on the right, 2 on the left). X-linked inheritance with expression in heterozygous females cannot be excluded.     

Familial congenital brachial palsy.

Eight relatives in a Sicilian family, including a sibship of 5, were affected with severe unilateral congenital brachial palsy (CBP) in a pattern suggesting autosomal dominant inheritance with reduced penetrance (6 cases affected on the right, 2 on the left). X-linked inheritance with expression in heterozygous females cannot be excluded.     

A novel mutation in TNNT3 associated with Sheldon-Hall syndrome in a Chinese family with vertical talus

Distal arthrogryposis (DA) is a group of rare, clinically and genetically heterogeneous disorders primarily characterized by congenital contractures of the limb joints. Recently, mutations in genes encoding the fast-twitch skeletal muscle contractile myofibers complex, including troponin I2 (TNNI2), troponin T3 (TNNT3), tropomyosine 2 (TPM2), and embryonic myosin heavy chain 3 (MYH3), and the slow-twitch skeletal muscle myosin binding protein C1 (MYBPC1) were confirmed to cause DA1, DA2A, and DA2B. DA2B, or Sheldon-Hall syndrome (SHS; MIM 601680), is intermediate to DA1 and DA2A, or Freeman-Sheldon syndrome (FSS; MIM193700), and shows prominent facial traits. This report describes a Chinese family with SHS over three generations in which all affected individuals showed vertical talus and one demonstrated preauricular tags on the face. Linkage analysis and PCR sequencing revealed a novel substitute mutation at a hot-spot site in TNNT3 (c.187C > T; p.R63C). This mutation was confirmed to cosegregate with the DA phenotype in affected individuals. SIFT and PolyPhen analyses suggest that the mutation is pathogenic. We report this mutation in TNNT3 and speculate that bilateral vertical talus, or severe clubfoot, might be a special characteristic for cases with the TNNT3 R63C mutation.     

Neuroimaging fails to identify asymptomatic carriers of familial porencephaly

Familial porencephaly is a rare condition usually transmitted as an autosomal dominant trait with incomplete penetrance. We describe a new family in which six members across four generations had congenital hemiplegia. Cerebral imaging was performed in three patients and showed porencephaly in all cases. In order to provide effective genetic counseling, three asymptomatic carriers were investigated by cerebral computerized tomography (three patients) and cerebral magnetic resonance imaging (one patient). These investigations failed to show any congenital abnormalities. We conclude that cerebral imaging is unreliable to detect obligate carriers of familial porencephaly.     

Incomplete penetrance and expressivity skewing in hereditary multiple exostoses

Hereditary multiple exostosis (EXT) is an autosomal dominant skeletal disorder characterized by the formation of cartilage-capped prominences developing from the juxta-epiphyseal regions of the long bones and causing orthopedic deformities and occasionally sarcomatous degeneration. Reviewing a large cohort of 175 EXT patients referred to us over the last 40 years (1955–1995), we found 109 familial forms (62%) and 66 isolated cases (38%). The disease is consistently diagnosed before the age of 12 years and the risk of malignancy, although increased, is quite modest in our series (0.57%). The observation of seven unaffected individuals (six females, one male) with a family history and affected offspring supports the incomplete penetrance of the disease. Moreover, the observation of an unequal sex-ratio with a preponderance of males among probands in this series (103: 72, p < 0.02) and in all series reported to date (198: 133, p < 0.001) gives support to the variable penetrance of EXT genes among sexes. Whether this incomplete penetrance is associated with one of the disease genes recently identified in EXT is currently under investigation.     

Dominant mesomelic dysplasia, ankle, carpal, and tarsal synostosis type: a new autosomal dominant bone disorder.

A new type of mesomelic dysplasia was in 3 generations of a large Thai family. It is characterized by bilateral symmetrical marked shortening of the ulnae and shortening and bowing of the radii. The proximal fibula is usually short and synostoses are present between the tibia and fibula and the small malformed calcaneus and talus. The prominent calcanei on the ventral surfaces of the distal fibulae are a characteristic feature of the new type. Carpal and tarsal synostoses are present in some affected people. All affected individuals walk on the tips of their toes with the dorsal foot deviated laterally. The deformities of the radius and ulna somewhat resemble those of mesomelic dysplasia, Langer type, but otherwise the condition is distinctly different. This new mesomelic dysplasia is an autosomal dominant trait with complete penetrance and variable expressivity over 3 generations.     

A large family with patent ductus arteriosus and unusual face.

A large family is described in which patent ductus arteriosus in association with an unusual facial appearance affected nine family members in three generations. The segregation pattern suggests autosomal dominant inheritance with incomplete penetrance with respect to the PDA. The facial features included a broad, high forehead, flat profile, and short nose with a broad, flattened tip.     

Dominant mesomelic dysplasia,ankle, carpal,and tarsal synostosis type: A new autosomal dominant bone disorder

A new type of mesomelic dysplasia was in 3 generations of a large Thai family. It is characterized by bilateral symmetrical marked shortening of the ulnae and shortening and bowing of the radii. The proximal fibula is usually short and synostoses are present between the tibia and fibula and the small malformed calcaneus and talus. The prominent calcanei on the ventral surfaces of the distal fibulae are a characteristic feature of the new type. Carpal and tarsal synostoses are present in some affected people. All affected individuals walk on the tips of their toes with the dorsal foot deviated laterally. The deformities of the radius and ulna somewhat resemble those of mesomelic dysplasia, Langer type, but otherwise the condition is distinctly different. This new mesomelic dysplasia is an autosomal dominant trait with complete penetrance and variable expressivity over 3 generations. © 1992 Wiley-Liss, Inc.     

Family studies of infantile visceral myopathy: A congenital myopathic pseudo-obstruction syndrome

We conducted family studies of a rare congenital myopathic pseudo-obstruction to provide recurrence risks to families of affected children. This infantile visceral myopathy (IVM) involves the smooth muscles of the digestive tract and frequently the urinary bladder. Family and pregnancy histories from 16 families were evaluated to identify possible environmental or genetic components. The families were ethnically and geographically diverse within the United States. Eleven of the children were alive, four had died, and the status of one was unknown. The sex ratio was 5 females to 11 males. The pregnancy histories provided no evidence of a teratogenic cause. In one family, the disorder passed from parent to child. There were no consanguineous matings, no similarly affected sibs, and except for one case, the family histories did not suggest affected relatives. We suspect a new dominant mutation may be responsible for some cases of IVM, whereas in others, IVM may be caused from a dominant gene with variable expressivity and incomplete penetrance. Therefore, we predict the recurrence risk of severely affected children is much less than the 25 or 50% risk sometimes given families based on the assumption of autosomal recessive or autosomal dominant inheritance. When counseling IVM families, a thorough family history is essential. Subsequent pregnancies should be monitored by ultrasound for megacystis that was detected prenatally in seven of these cases. Am. J. Med. Genet. 82:114–122, 1999. © 1999 Wiley-Liss, Inc.     

Exome sequencing identifies ZFPM2 as a cause of familial isolated congenital diaphragmatic hernia and possibly cardiovascular malformations

Using exome sequencing we identify a heterozygous nonsense mutation in ZFPM2 as a cause of familial isolated congenital diaphragmatic hernia in 2 affected siblings. This mutation displays variable phenotypic expression being present in a third sibling with a mild diaphragmatic eventration and a cardiovascular malformation. The same variant is seen in 2 additional family members, both of whom are asymptomatic, thus highlighting that ZFPM2 haploinsufficiency is associated with reduced penetrance. Our finding adds further evidence for ZFPM2 having a role in diaphragm and cardiovascular development.     

Essential tremor, nystagmus and duodenal ulceration. A "new" dominantly inherited condition.

The familial occurrence of essential tremor combined with (congenital) nystagmus, duodenal ulceration and a narcolepsy-like sleep disturbance caused by an autosomal dominant gene with high penetrance and fairly uniform expressivity is reported in a family of Swedish-Finnish ancestry. Twelve of 17 affected family members had essential tremor which began between 30-40 years of age and which could be controlled temporarily by alcohol; this resulted in alcoholism in several affected individuals. The most severly affected persons showed cerebellar signs which may reflect a possible pathogenetic relationship of the syndrome to the genetic cerebellar atrophies. Nystagmus, observed in 12 of 17 affected family members (eight of whom were also affected with tremor) usually was congenital and accompanied by refractive errors. Duodenal ulcers occurred almost exclusively in individuals with the neurological syndrome, and preceded its onset in some cases. The ulcer disease therefore seems to be a component manifestation of the syndrome and is interpreted as a pleiotropic effect of the gene which also causes the nystagmus, tremor and sleep disturbance.     

Partial penetrance and phenotypic variability of aplasia of lacrimal and salivary glands caused by a novel FGF10 donor splice-site mutation

Thirteen affected individuals of six generations of a single kindred presented with epiphora evident from infancy. Physical exam and Schirmer test revealed variable expression of tear deficiency, congenital punctal atresia, and dry mouth with multiple caries, without concomitant abnormalities of the ears or digits, commensurate with a diagnosis of aplasia of the lacrimal and salivary glands (ALSG). Reconstruction of the upper lacrimal drainage system was performed in some of the affected individuals. Genetic analysis, testing six affected individuals and three non-affected family members, identified a single novel heterozygous splice-site variant, c.429 + 1, G > T in fibroblast growth factor 10 (FGF10) (NM_004465.1), segregating throughout the family as expected for dominant heredity. RT-PCR assays of HEK-293 cells transfected with wild type or mutant FGF10 demonstrated that the variant causes skipping of Exon 2. Notably, individuals sharing the same variant exhibited phenotypic variability, with unilateral or bilateral epiphora, as well as variable expression of dry mouth and caries. Moreover, one of the variant carriers had no ALSG-related clinical findings, demonstrating incomplete penetrance. While coding mutations in FGF10 are known to cause malformations in the nasolacrimal system, this is the second FGF10 splice-site variant and the first donor-site variant reported to cause ALSG. Thus, our study of a unique large kindred with multiple affected individuals heterozygous for the same FGF10 variant highlights intronic splice-site mutations and phenotypic variability/partial penetrance in ALSG.     

Familial idiopathic premature ovarian failure: an overrated and underestimated genetic disease?

The incidence of familial cases of premature ovarian failure varies from 4 to 31%. Recall bias may explain part of the variance. Thorough evaluation of alleged affected relatives showed a lower incidence than the original family history suggested. In the present study the incidence of familial cases was 12.7%. Pedigree studies on affected families showed a mode of inheritance suggestive of autosomal dominant sex-limited transmission or X-linked inheritance with incomplete penetrance. An adequate family history can distinguish between familial or sporadic premature ovarian failure. The risk of female relatives developing premature ovarian failure may be as high as 100% in familial premature ovarian failure, or as low as 1% in sporadic cases.